Cellular and Molecular Life Sciences (2019) 76:3167–3191

https://doi.org/10.1007/s00018-019-03178-2 Cellular and Molecular Life Sciences

REVIEW

Metalloproteinases and their tissue inhibitors in Alzheimer’s disease

and other neurodegenerative disorders
Santiago Rivera1   · Laura García‑González1 · Michel Khrestchatisky1 · Kévin Baranger1

Received: 22 May 2019 / Revised: 22 May 2019 / Accepted: 29 May 2019 / Published online: 13 June 2019
© Springer Nature Switzerland AG 2019

Abstract
As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effec-
tive treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the
progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate
the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of met-
alloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with
thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an
increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood–brain barrier disruption,
protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue
inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support
neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge
on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer’s disease,
Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease.

Keywords  Parkinson’s disease · Huntington’s disease · Amyotrophic lateral sclerosis · ADAM · TIMP · Neurodegenerative
brain disease

Abbreviations CSF Cerebrospinal fluid

6-OHDA 6-Hydroxydopamine CTF C-terminal fragment
5xFAD Transgenic mice bearing 5 familial C99 APP-CTF of 99 amino acids
mutations on human App and Psen1 DAPT  N-[N-(3,5-Difluorophenacetyl)-
genes l-alanyl]-S-phenylglycine t-butyl
AD Alzheimer’s disease ester, γ-secretase inhibitor
Aβ Amyloid beta peptide DLB Dementia with Lewy bodies
ADAM A disintegrin and metalloproteinase ECM Extracellular matrix
ADAMTS ADAMs with thrombospondin motifs  FADD Fas-associated protein with death
ALS Amyotrophic lateral sclerosis domain
APOE Apolipoprotein E HD Huntington’s disease
APP Amyloid precursor protein HD-NSCs Neural stem cells from HD patients
BACE-1 Beta-site APP cleaving enzyme 1 HEKswe Human embryonic kidney cells that
BBB Blood–brain barrier express App gene with the Swedish
C3 BACE-1 inhibitor IV mutation
CAA​ Cerebral amyloid angiopathy Htt Huntingtin
CNS Central nervous system ICV Intracerebroventricular
IDE Insulin degrading enzyme
* Santiago Rivera IL-1 Interleukin-1
santiago.rivera@univ‑amu.fr LBs Lewy bodies
LDLR Low-density lipoprotein receptor
1
Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol,
Marseille, France

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LRP-1 Low-density lipoprotein receptor-
related protein 1
LRRK2 Leucine-rich repeat kinase 2
LTP Long-term potentiation
MCP-1 Monocyte chemoattractant protein 1
MMP Matrix metalloproteinase
MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydro-
pyridine
MSC Mesenchymal stem cells
MT-MMP Membrane-type matrix
metalloproteinase
MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-di-
phenyl tetrazolium bromide
NFT Neurofibrillary tangles
NSC Neural stem cell
NTF N-terminal fragment
PD Parkinson’s disease
PGRN Progranulin
Psen 1 and Psen 2 Presenilin 1 and 2
RAGE Receptor for advanced glycation end
products
sAPPα/β Soluble APPα/β
TIMP Tissue inhibitor of metalloproteinases
TNF-α Tumour necrosis factor α
TREM2 Triggering receptor expressed on
myeloid cells 2
Introduction
Humans have not evolved to last long in nature. As the forces
of natural selection disappear with the improvement of life
and health conditions, average life expectancy has exceeded
80 years in many countries of the world. The concomitant
consequence is the soaring of aging-related neurodegenera-
tive disorders that cannot be cured or significantly slowed
down, thereby affecting millions of patients and even more
caregivers. These disorders generally start with mild symp-
toms that alter motor, behavioural and cognitive functions.
The gradual loss of large amounts of neurons inevitably
leads to a worsening of these symptoms, which often end
up with a loss of global autonomy before the patient’s death.
Neurodegenerative diseases are associated with genetic and
environmental stimuli that act in synergy to elicit disease-
specific dysfunctions, but also share fundamental common-
alities: free radicals generation, mitochondrial dysfunction,
immunosenescence, protein misfolding or inflammation.
The confluence of these pathogenic driving forces makes
it difficult to identify a single cause that could be more eas-
ily targeted. It is of the utmost importance to elucidate the
underlying mechanisms of the pathology to clearly iden-
tify molecular targets and help design effective therapeu-
tic strategies. Among the biofactors that can contribute to
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S. Rivera et al.
neurodegenerative processes, matrix metalloproteinases
(MMPs) are of particular interest because: (1) MMPs are
expressed by all types of central nervous system (CNS) cells;
(2) MMPs expression is modulated by potentially neuro-
toxic proteins, which can in turn undergo cleavage and func-
tional regulation by these same MMPs; (3) MMPs modulate
chronic neuroinflammation through cleavage of inflamma-
tory mediators (i.e., cytokines and chemokines) and tight
junction proteins that ensure blood–brain barrier (BBB)
impermeability; (4) MMPs control the processing of extra-
cellular matrix (ECM) and transmembrane proteins involved
in cell–cell interactions; (5) MMPs can initiate or be part of
proteolytic cascades that amplify cellular responses in a web
of interactions between numerous enzymes and substrates.
In this review, we will discuss the most relevant knowl-
edge on MMPs and their physiological inhibitors, the tissue
inhibitors of metalloproteinases (TIMPs), in four neurode-
generative diseases that strike in mid–late-life: Alzheimer’s
disease (AD), Parkinson’s disease (PD), amyotrophic lat-
eral sclerosis (ALS) and Huntington’s disease (HD). We will
also discuss to a lesser extent the contribution of two other
metalloproteinase subfamilies, which, like MMPs, belong
to the superfamily of metzincins: a disintegrin and metal-
loproteinase (ADAM) and ADAMs with thrombospondin
motifs (ADAMTS). While ADAMs are membrane-anchored
enzymes, chiefly considered as sheddases of membrane
proteins, ADAMTS are mostly extracellular matrix (ECM)-
degrading enzymes. ADAMs and ADAMTS in the nervous
system are extensively discussed in this CMLS special issue
by Hsia and colleagues [1] and elsewhere [2].
Metalloproteinases and natural tissue
inhibitors of metalloproteinases
Matrix metalloproteinases
Twenty-four proteinases constitute the MMP family in
humans. According to their structure and substrate specific-
ity, this multigenic family have been traditionally classified
into five categories: gelatinases (-2 and -9), stromelysins
(MMP-3 and -10), collagenases (MMP-1, -8 and -13), mem-
brane-type MMPs (MT-MMPs, MMP-14, -15, -16, -17, -24
and -25) and the other MMPs, e.g., MMP-7, MMP-12 or
MMP-28 (see for reviews [2–4]). Widely expressed in all
human cells, MMPs have significant structural homology
and this is one of the main reasons that hinder the develop-
ment of specific inhibitors against each of them. All MMPs
possess a 17–29 amino acid hydrophobic signal peptide that
targets the proteinase to the secretory pathway, followed by
a pro-domain sequence of 77–87 amino acids that interacts
with a conserved cysteine residue and the Z ­ n2+ cation of
the catalytic site, thereby maintaining the enzyme under
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other…
a zymogen inactive state. The catalytic domain of ~ 170
amino acids, harbours a ­Zn2+ binding consensus sequence
HExxHxxGxxH with three histidine residues that confer
­ n2+. Redox-mediated break-up of the interac-
stability to Z
tion between the cysteine and the metal cation as well as
propeptide removal by autocatalysis or by other proteinases,
triggers the conversion of inactive pro-MMPs into active
MMPs by a mechanism known as “cysteine switch”. Down-
stream of the catalytic site, a short hinge region followed
by the hemopexin domain (~ 200 amino acids) exhibits a
relatively variable amino acid sequence, which is crucial for
proteinase-substrate specificity. Of note, MMP-7, MMP-23
and MMP-26 lack the hemopexin domain. In addition to this
multidomain common structure, the six members of the MT-
MMP subfamily contain membrane anchoring domains; a
glycosylphosphatidylinositol in the case of MMP-17 (MT4-
MMP) and MMP-25 (MT6-MMP) or a transmembrane
domain with a short intracytoplasmic moiety in the case of
MMP-14 (MT1-MMP), MMP-15 (MT2-MMP), MMP-16
(MT3-MMP) and MMP-24 (MT5-MMP). Moreover, MT-
MMPs, MMP-11, MMP-23 and MMP-28 contain a specific
di-basic sequence at the end of the pro-domain, which is
recognized by the intracellular ­Ca2+-dependent serine pro-
teinase furin, leading to activation of these enzymes in the
trans-Golgi network [4].
MMPs have been usually considered as ECM-degrading
enzymes. This view is now changing with the growing
number of non-matrix substrates identified among signal-
ling molecules, trophic factors, receptors, cell adhesion
molecules, and even nuclear proteins [5–7]. It must be
emphasized that MMPs are more and more involved in the
modulation of neuroinflammatory processes common to
many nervous system pathologies through the regulation of:
(1) ECM proteolysis [8]; (2) cell proliferation, differentia-
tion and migration [9–11]; (3) activation and inactivation of
inflammatory mediators [12]; (4) BBB permeability [13].
If we add that proteolytic-independent effects of MMPs are
beginning to be unveiled [14], we can conclude that MMPs
represent a paradigm of extraordinary and fascinating func-
tional diversity.
Tissue inhibitors of metalloproteinases
TIMPs are pleiotropic secreted proteins, mostly known for
their reversible MMP inhibitory activities. The four TIMPs
(TIMP-1 to TIMP-4) share 40% of sequence homology
and a backbone with twelve conserved cysteine residues
and six disulfide bonds that are essential for their biologi-
cal activities. Besides the signal peptide, TIMPs structure
comprises a N-terminal inhibitory domain of MMPs and
a C-terminal domain of interaction. TIMP-1, -2 and -4
are found as soluble or cell surface-associated proteins,
whereas TIMP-3 preferentially binds to ECM proteins. In
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general, TIMPs bind all MMPs and some ADAMs, but
only TIMP-3 appears to have inhibitory activity against
ADAMTS [15]. The N-terminal domain of TIMPs is suf-
ficient to inhibit MMPs, but in the case of ADAM10,
TIMP-1 and TIMP-3 also require the interaction of their
C-terminal domain with the proteinase. ADAM10 is not
inhibited by TIMP-2 and -4 [16]. The binding affinities
between TIMPs and MMPs or their modes of interaction
differ significantly. For instance, TIMP-1 inhibits soluble
MMPs and ADAM10/17, but it is a very poor inhibitor of
MT-MMPs. Also, TIMP-1 is able to specifically bind the
hemopexin domain of pro-MMP-9, although the biological
function of this complex is unknown [17]. TIMP-2 inhibits
both soluble and membrane-bound MMPs. In addition,
TIMP-2 specifically binds to the hemopexin domain of
pro-MMP-2, paradoxically leading to the activation of the
enzyme on the plasma membrane; indeed, the N-terminal
domain of TIMP-2 interacts with MT1-MMP, whereas
the C-terminal domain binds to the hemopexin domain of
pro-MMP-2, thus fixing the pro-MMP-2 on the membrane
and allowing its activation by cleavage of the pro-peptide
by an adjacent MT1-MMP [18]. TIMP-3 inhibits MMPs,
ADAMs and ADAMTS. TIMP-4 has the same inhibitory
profile as TIMP-2. All TIMPs are ubiquitously distributed,
with the exception of TIMP-4, which is predominantly
expressed in heart, ovary and brain [19].
Timp-1, Timp-3 and Timp-4 genes are nested in introns of
genes coding for synaptic proteins synapsins and Timp-2 is
close to the synapsin IV gene [20–22]. The intriguing genetic
link between TIMPs and synapsins likely underlines func-
tional relations of these proteins in the nervous system that
need to be explored, as many neuropathological conditions
show significant alterations of their expression.
Alzheimer’s disease
Alzheimer’s disease (AD) is the most common type of neu-
rodegenerative disorder for which we still lack efficient cur-
ing, slowing or preventing treatments. Prototypic symptoms
of AD start with short-term mild memory deficits that dete-
riorate with time, progressively leading to severe memory
loss, changes in mood, anxiety, depression, agitation, spatial
disorientation, motor impairment, and finally dementia. AD
affects 45 million people currently worldwide and this figure
is expected to rise to 131 million in 2050 unless efficient
treatments are found in the meantime [23]. Only a handful of
available drugs can transiently and moderately limit clinical
symptoms in the early stages of the disease (https:​ //www.alz.
org/alzhe​imers​-demen​tia/resea​rch_progr​ess/treat​ment-horiz​
on). The difficulty in finding effective treatments for AD is
due to a multitude of factors, including:
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• The multifactorial etiology of AD. Familial forms of the
disease represent ~ 1% of cases and are caused by muta-
tions in 3 genes: amyloid precursor protein (App), and
presenilins 1 (Psen1) and 2 (Psen2). The overwhelming
majority of patients suffer from sporadic forms of the
disease of unknown etiology, where genetic and environ-
mental risk factors likely synergize with age to prepare a
fertile ground for the development of the disease.
• The difficulty of successfully reproducing valuable pre-
clinical data in human clinical trials.
• Comorbidity with other disorders/injuries may add con-
founding factors from an etiological standpoint.
• A relatively poor knowledge of the pathophysiological
mechanisms involved. To date, most research efforts have
focused on studying two pathological characteristics of
the disease: the accumulation of the amyloid beta peptide
(Aβ) resulting from the proteolytic processing of APP,
and the hyperphosphorylation of the tau protein (p-tau).
Unfortunately, the results of clinical trials targeting Aβ
or p-tau have been well below expectations [24–26],
prompting researchers to discover alternative targets.
• Clinical trials are conducted on older people after diag-
nosis, but AD starts 10 or 15 years earlier, meaning that
treatments against relevant targets (e.g., Aβ, p-tau) occur
too late, when the aging brain has already lost much of
its healing ability and resilience.
Despite the diversity of potentially pathogenic mecha-
nisms in AD, metalloproteinases have been mainly involved
in the metabolism of APP and Aβ. It is in this context that
we will address the following sections.
Main pathogenic pathways linked to APP processing
and amyloidogenesis
Almost 30 years after its publication, the amyloid hypothesis
of AD remains a valuable tool to study the underlying patho-
physiological mechanisms, despite the failure of clinical tri-
als based on its principles. The amyloid hypothesis essen-
tially asserts that excessive accumulation of Aβ is a major
pathogenic determinant (see for an updated review [27]). Aβ
results from sequential cleavage of APP by two canonical
secretases; β-secretase (beta-site APP cleaving enzyme-1,
BACE-1) generates a transmembrane fragment of 99 amino
acids (C99), which is then cleaved by the γ-secretase com-
plex, thus releasing 4 kDa Aβ monomers, mainly 40 (Aβ40)
and 42 (Aβ42) amino acids. Aβ42 aggregates more easily
than Aβ40 and it is, therefore, more toxic. Monomers can
assemble into oligomers, protofibrils and fibrils, which will
eventually give rise to amyloid plaques. Although the lat-
ter are a hallmark of AD and provide bona fide post mor-
tem diagnostic, small size oligomers (e.g., dimers, trimers)
are increasingly seen as the most toxic forms of Aβ [28].
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S. Rivera et al.
APP cleavage by β- and γ-secretases occurs following APP
endocytosis into the endosomes or during APP targeting to
the cell surface through the trans-Golgi network, thereby
highlighting the importance of APP cellular trafficking in
amyloidogenesis (reviewed in [29]). Aβ accumulation results
from a balance between its formation and its degradation/
clearance. Several metalloproteinases, including insulin
degrading enzyme (IDE), angiotensin converting enzyme,
endothelin converting enzyme and neprilysin, play a prime
role in Aβ degradation (reviewed in [30]). Moreover, some
MMPs (i.e., MMP-2, -3, -9 and MT1-MMP) have also been
reported to display Aβ-degrading activity (see [3]). Com-
plementary to proteolytic degradation, the neurovascular
hypothesis of AD suggests that tuning down Aβ levels in
the brain parenchyma can also be achieved by scavenging
systems mostly operating in the BBB microenvironment.
Several reports indicate that one of these systems is the
apolipoprotein E (APOE) receptor, low-density lipoprotein
receptor (LDLR). Thus, overexpression of LDLR in the
mouse brain limits amyloid plaque formation and enhances
Aβ clearance from brain to blood [31, 32], as well as Aβ
uptake and degradation by astrocytes through a mechanism
where Aβ directly binds to LDLR, even in the absence of
APOE [33]. The low-density lipoprotein receptor-related
protein 1 (LRP-1), mainly expressed by glial and endothe-
lial cells, also contributes to Aβ clearance. This is confirmed
by experiments in which the decrease/abrogation of LRP-1
expression using antisense oligonucleotides [34] or LRP-
1-conditional knockout [35], interferes with Aβ clearance
via the BBB, leading to its accumulation in the brain and the
consequent learning deficits. Selective knockdown of LRP-1
in astrocytes also reduces Aβ uptake and degradation, which
correlates with a downregulation of major Aβ-degrading
enzymes MMP-2, MMP-9 and IDE [36]. Unlike, LDLR and
LRP-1, the receptor for advanced glycation end products
(RAGE) promotes Aβ influx from blood-to-brain (reviewed
in [37]). Accordingly, silencing or eliminating RAGE has
been shown to preserve BBB integrity in vitro [38] and
reduce brain Aβ levels in transgenic AD mice by decreas-
ing β- and γ-secretase activities [39].
It is clear that neurotoxicity derived from APP cleavage
can no longer be considered exclusively on the basis of Aβ
accumulation. Other APP metabolites generated by different
proteinases (e.g., MT-MMPs, δ-secretase) also contribute to
Alzheimer’s pathology (reviewed in [40]), paving the way
for an assessment of APP breakdown products as compo-
nents of pathogenic pathways, and therefore, as potential
new therapeutic targets.
Non‑pathogenic pathways linked to APP processing
In physiological conditions, APP is mainly processed at
the plasma membrane level by α-secretases of the ADAM
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other…
family. This subfamily of metzincins present structural and
functional similarities with MMPs (see for review [2]).
ADAM10 is the main physiological/constitutive α-secretase
[41, 42], while ADAM17 has been identified as responsi-
ble of the regulated α-secretase activity [43]. α-secretase
cleavage in the middle of the Aβ sequence prevents its for-
mation and concomitantly generates a soluble N-terminal
APP fragment (sAPPα) with neurotrophic and neuroprotec-
tive properties [44, 45]. Aβ oligomers stimulate transient
increase of sAPPα levels and α-secretase activity in cultured
cortical neurons, which could be interpreted as a cell self-
defence mechanism [46]. While there is little doubt about the
neurotoxicity of Aβ accumulation, the physiological roles
of the peptide are still poorly understood. Several pieces
of evidence converge to show that Aβ is part of the innate
immunity arsenal to fight against bacterial, fungal and viral
pathogens in the brain [47–50]. Moreover, physiological Aβ
is involved in maintaining basal neurotransmitter release and
synaptic activity [51]. It has been shown that picomolar con-
centrations of Aβ are sufficient to stimulate learning and
memory in healthy rodents as well as long-term potentiation
(LTP)—a form of synaptic plasticity considered to be a cel-
lular substrate for learning—through the activation of nico-
tinic receptors [52–54]. N-terminal fragments of Aβ found in
the cerebrospinal fluid (CSF) of healthy and AD individuals
appear to be determinant for these physiological effects, with
the YEVHHQ motif located before the α-cleaving site in the
Aβ sequence playing a prominent role [55]. It has also been
shown that cGMP nucleotide stimulates the release of Aβ
by facilitating the approximation in endolysosomal compart-
ments between APP and BACE-1, the main β-secretase. The
blockade of Aβ with antibodies in these conditions inter-
feres with cGMP-induced enhancement of LTP and memory
[56]. Taken together, these data indicate that the proteolytic
regulation of Aβ transcends the idea of its neurotoxicity and
raises the question of the potential clinical consequences of
lowering Aβ levels below a physiological threshold.
MMPs are mainly considered as Aβ‑degrading
enzymes, but not only
MMPs with Aβ‑degrading activity might be beneficial
Pioneer work in the 90’s linked for the first time AD with
MMPs. Tökés and collaborators found upregulated expres-
sion levels of inactive pro-MMP-9 in hippocampal neurons
of post mortem AD patients. They also demonstrated by
mass spectrometry the ability of active MMP-9 to cleave
Aβ40 on 3 sites of the membrane-spanning domain, but also
at ­Lys16–Leu17, the so-called α-cleavage site [57]. In the first
case, MMP-9 could prevent the formation of the neurotoxic
β-sheet. In the second, MMP-9 could act as an α-secretase.
Consistent with this idea, MMP-9 overexpressing mice
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exhibit increased levels of sAPPα associated with enhanced
LTP and enhanced learning and memory capabilities [58].
Other authors have corroborated in  vitro the ability of
MMP-9 to cleave soluble Aβ at the α-site, but the enzyme
seems to be more efficient at cleaving in the C-terminus with
decreasing processing efficiency towards the N-terminus to
generate fragments ending at positions 34, 33, 30, 23, 20 and
16 [59, 60]. In addition, MMP-9 exhibits a rather uncom-
mon feature among Aβ-degrading enzymes because it can
cleave preformed Aβ fibrils and compact amyloid plaques, as
shown on brain slices from APP/PS1 transgenic mice [59].
This further adds to the possibility that promoting MMP-9
activity may hold therapeutic potential. However, this pos-
tulate is subject to caution as it cannot be excluded that
proteolytic degradation of plaques could release toxic Aβ
assemblages and other neurotoxins contained in their mesh.
MMP-2 presents Aβ-degrading profiles roughly similar to
those reported for MMP-9, although MMP-2 appears to be
more efficient in cleaving Aβ42 [60].
Reactive astrocytes produce MMP-2 and MMP-9 and are
systematically associated with Aβ deposits in transgenic
mouse models of AD and in post mortem AD brains. In
support of a functional link between both observations, the
incubation of recombinant Aβ in conditioned media from
cultured mouse astrocytes yields breakdown Aβ C-terminal
fragments, which can be prevented by selective chemical
inhibitors of MMP-2 and MMP-9, and by TIMP-1 [61].
Furthermore, MMP-9 and MMP-2 knockout mice exhibit
higher levels of Aβ in the brain compared to wild-type mice,
thereby supporting that both MMPs degrade Aβ in vivo [61].
In the same vein, a recent study conducted to investigate
the impact of physical activity on Alzheimer’s pathology
reported that exercise training in Tg2576 transgenic mice
significantly decreases the levels of Aβ40 in the cortex, and
Aβ42 in the cortex and hippocampus. Of note, decreased
Aβ concentration was concomitant with a rise in the lev-
els of five proteins involved in Aβ clearance, among which
MMP-9 [62].
In addition to MMP-2 and MMP-9, other MMPs can also
degrade Aβ. For instance, metal ligand clioquinol stimulates
Aβ degradation in a cell culture system through a mecha-
nism involving the activation of MMP-3 [63]. MMP-7 was
recently reported to cleave Aβ40 and Aβ42, a process that
is inhibited by binding of Aβ to C ­ u2+ [64]. Concerning
membrane-anchored MMPs, it was shown that COS cells
overexpressing MT1-MMP degrade exogenous soluble Aβ40
and Aβ42, and release 6 different Aβ-derived peptides with
cleavage sites mostly located around the α-site, between
residues 12 and 18 of the Aβ sequence. Moreover, a soluble
variant of MT1-MMP lacking the transmembrane domain
was able to degrade in situ parenchymal amyloid plaques
in brain slices of Tg2576 mice [65], a feature shared only
with MMP-9, neprilysin and IDE among metalloproteinases.
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MMPs can be pathogenic in connection with inflammatory
processes
Although the degrading action of MMPs on Aβ could in
principle be considered beneficial, MMPs are multifunc-
tional enzymes, whose roles may depend not only on the cell
types that express them, but also on the substrates involved
or the pathological and spatio-temporal context (see for
review [2]). In the case of BBB disruption, MMPs have a
prominent role as they can proteolyse major components of
the basement membranes and tight junctions (see for review
[66] in this special CMLS issue). The impermeability of
BBB, which ensures selective exchanges between the cen-
tral and peripheral nervous systems, is compromised in AD
patients [67] and in transgenic AD mice [68]. This may con-
tribute to inflammatory and neurodegenerative processes,
probably with the participation of resident brain immune
cells, as suggested by a study using a co-culture of endothe-
lial cells and astrocytes exposed to Aβ42. In this work,
astrocyte-induced BBB opening was related to the activa-
tion of MMP-9 and the concomitant decrease in claudin-5,
a MMP-9 substrate that contributes to the maintenance of
functional tight junctions [69]. Another important source
of MMP, reactive microglia, may stimulate Aβ accumula-
tion through a MMP-9-dependent mechanism. In this case,
microglial MMP-9 generates C-terminal truncated Aβ frag-
ments that interfere with Aβ clearance across the BBB and
promote cerebral aggregation of intracranial-injected Aβ42
in wild-type mice. It is noteworthy that the seeding prop-
erties of these C-terminal fragments generated by MMP-9
could, therefore, contribute to the development of sporadic
forms of the disease [70]. Recently, another report pointed
out that disruption of the blood–CSF barrier 6 h after intrac-
erebral injection of Aβ oligomers was linked to conspicuous
inflammation, and was prevented by broad spectrum MMP
inhibitor GM6001 and by MMP-3 deficiency in mice, sug-
gesting that the control of MMP activity may have therapeu-
tic potential [71]. Likewise, Aβ42 oligomers dowregulated
tight junction scaffold proteins in an in vitro BBB model
using bEnd.3 endothelial cells. The weakening effects of
oligomers on BBB were blocked by either knocking down
RAGE, which was induced by Aβ42, or by GM6001 treat-
ment, which inhibited the activity of concomitantly upregu-
lated MMP-2 and MMP-9 [38]. GM6001 and another MMP
inhibitor, minocycline, also  proved to efficiently reduce
inflammation and oxidative stress associated with cerebral
amyloid angiopathy (CAA) in AD mice [72].
Blood-derived immune cells (e.g., macrophages, lympho-
cytes, granulocytes) are suspected to influence AD patho-
genesis, but the extent of their contribution to disease and
the underlying mechanisms remain elusive (for review [73]).
The question arises as to the role of immune cell MMPs,
provided that these cells can reach the brain parenchyma
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S. Rivera et al.
by diapedesis or through a disrupted BBB. Evidences in this
direction are rather limited at the moment. The monocytic
cell line THP-1 treated with Aβ42 releases more MMP-9,
along with tumour necrosis factor (TNF-α), interleukin-
1beta (IL-1β) and monocyte chemoattractant protein-1
(MCP-1), compared to untreated cells [74]. Purified neu-
trophils dramatically increase the production of MMP-9
in response to incubation with highly toxic Aβ25-35 [75].
Interestingly, neutrophils infiltrate the brain of AD patients
and are also observed in the brain parenchyma of transgenic
AD mice in areas with Aβ deposition [76].
Regulation of MMPs in Alzheimer’s animal models
and Alzheimer’s patients
The data above convincingly show that Aβ is a substrate
of MMPs. In turn, Aβ modulates the expression of MMPs,
probably revealing the existence of feedback regulatory
mechanisms. Since early work by Gottschall and collabo-
rators showing that Aβ40 could trigger the expression of
MMP-2, -3 and -9 in rat mixed neuronal/astrocyte cultures
[77], other authors have confirmed these data. Thus, astro-
cytes surrounding Aβ plaques in transgenic mice brains
show increased levels of MMP-2 and -9 [61]. The increase
in the mRNA of both gelatinases is already detected at
4 months of age in the hippocampus of 5xFAD mice, and
even earlier (2 months) in some astrocytes close to incipient
amyloid plaques [78]. On the other hand, MMP-9 immu-
nostaining is upregulated in the soma and dendrites of cor-
tical neurons in 2-month-old 5xFAD mice [78], indicating
altogether that the upregulation of MMP-2 and MMP-9 in
Aβ enriched areas starts at pre-symptomatic stages of the
pathology and persists over the prodromal-like and symp-
tomatic phases, as they have been defined in the 5xFAD
model [79]. Whether this conveys beneficial or detrimental
effects cannot be systematically anticipated, as functional
duality is a characteristic of both gelatinases. These might
be beneficial based on their Aβ-degrading properties, but
they might also promote BBB disruption and neuroinflam-
mation [80] or exert direct neurotoxicity in the hippocampus,
as reported for MMP-9 [81]. Along this line, AβE22Q and
AβL34V mutations associated with hemorrhagic symptoms
in early onset CAA stimulate the expression and activation
of MMP-2 by endothelial cells in a rather selective manner,
which is linked to possible BBB dysfunctions [82]. Moreo-
ver, Mizoguchi and collaborators demonstrated that intracer-
ebroventricular (ICV) injections of Aβ upregulated MMP-9
expression in neurons and astrocytes and triggered cogni-
tive deficits. Such deficits were efficiently prevented in mice
lacking MMP-9 and also after treatment with chemical MMP
inhibitors [83]. In addition to the extensive work on gelati-
nases, other MMPs have also attracted attention in the field.
MT1-MMP content was found increased in neurons and
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other…
amyloid plaques of 5xFAD mice at 6 months of age—dur-
ing the symptomatic phase of the pathology—this increase
affecting both the active and inactive forms of MT1-MMP
[78]. Other authors have shown that MT1-MMP expression
is mainly associated with reactive microglial cells in 5xFAD
mice [84] and reactive astrocytes in Tg-SwDI transgenic AD
mice [65]. Morevoer, Aβ42 increases the mRNA levels of
MMP-3, -12 and -13 in a microglial cell line and in primary
murine microglia in a PI3/Akt dependent manner [85]. The
expression of MMP-1, for which no involvement in APP/Aβ
metabolism is known, correlates with neuronal degeneration
in the rat hippocampus 1 month after ICV injection of Aβ25-
35 [86]. Taken together, these data consistently indicate the
upregulation of MMP levels after exposure to exogenous
Aβ or in the vicinity of Aβ deposits in transgenic mice, with
spatial distributions that may vary depending on the cell type
or animal model studied.
Studies in humans mostly reflect the upward trend in
MMP levels, although some declines have been noted.
Human cerebrovascular smooth muscle cells, constituents
of the BBB, show increased expression of MMP-2 and its
activating enzyme MT1-MMP after Aβ treatment in culture,
which eventually results in increased MMP-2 activity and
reduced cell viability [87]. Oligomers of Aβ42 positively
regulate the expression of several MMPs (i.e., MMP-1, -3,
-9, -10, -12 and -19) in microglia isolated from the brain
of AD patients post mortem, compared to controls without
dementia [88]. ELISA assay revealed MMP-1 levels signifi-
cantly elevated by more than 50% in different cortical areas
of AD patients [89]. Also in post mortem brain tissue, MT5-
MMP immunostaining was detected in amyloid plaques [90]
and MT1-MMP in microglial cells neighbouring plaques
[84], while MMP-3 was found in both amyloid plaques and
the interstitium between myelinated axons and astrocytes, in
particular, in the parietal cortex [91]. The concentrations of
MMP-3 are higher in the CSF of AD patients compared to
healthy controls, in contrast with MMP-9 whose levels are
lowered in the AD condition [92]. Similarly, Horstmann and
collaborators reported an increase in the levels of MMP-3
in CSF and plasma of AD patients, whereas MMP-2 and
MMP-9 decrease in plasma [93]. Interestingly, Lorenzl and
collaborators found consistent increased MMP-9 levels in
plasma in two studies [94, 95] and another study also showed
increased MMP-9/TIMP-1 ratios in CSF from AD patients
[96]. Noticeably, this study reported increased MMP-3 and
MMP-9 levels, as well as increased MMP-3/TIMP-1 ratio,
in the CSF of non-demented individuals carrying AD risk
markers (e.g., p-tau, Aβ42 or APOE ε4 allele). A negative
correlation was found between plasma levels of MMP-3
and the mini-mental state examination score that assesses
cognitive performance [97]. Such negative correlation was
also confirmed in the plasma of AD patients for MMP-3
activity measured by casein zymography. Consistent with
3173
elevated plasma levels of MMP-3, its substrate gelsolin was
decreased in these samples, suggesting that the combined
use of gelsolin and MMP-3 could, therefore, hold potential
as a plasma biomarker in AD [98]. Even accepting that cor-
relative data do not allow for a causal link between MMP
levels and disease progression, it has been proposed that pro-
teolysis limits the amount of circulating Aβ that could reach
the brain. This idea is based on the ability of MMPs and
ADAMs (e.g., MT1-MMP, MMP-9, ADAM10, ADAM12
and ADAM17) to shed RAGE or LRP-1 [99–103], with the
consequent release of the soluble truncated receptors that
can bind circulating Aβ; it is estimated that 70% of circulat-
ing Aβ40 and 90% of Aβ42 is bound to soluble LRP-1 [104].
Most reports associate MMPs to APP metabolism in AD,
however, recent work also unveils the possibility of func-
tional links between MMPs and tau protein. For example,
increased levels of active MMP-2 colocalize with p-tau in
neurofibrillary tangles (NFT) and dystrophic neurites in
the entorhinal cortex of AD patients at early disease stages
[105]. The same study reports that MMP-2 can cleave
recombinant tau in vitro, but fails to cleave tau contained in
NFT, leading to the speculation that inactivation of MMP-2
in NFT might prevent the formation of toxic truncated tau
assemblies. MMP-9 and MMP-3 are also described as tau-
degrading enzymes, but only MMP-9 can generate fragments
prone to generate tau oligomers, which are increasingly con-
sidered as the most toxic forms of tau [106]. MMP-3 and
MMP-10 levels correlate with tau or p-tau levels in the CSF
of AD patients, further stressing the potential interest of
MMPs as biomarkers of AD pathology [97, 107].
Overall, these data illustrate a wide range of mechanisms
by which MMPs can have beneficial or detrimental effects
on AD. Particular mention is given in the following section
to MT-MMPs, which are relatively new enzymes in the field
of AD and open new avenues for a better understanding of
pathophysiology.
Alternative processing of APP by MT‑MMPs
and contribution to Alzheimer’s pathogenesis
Early work from Higashi and Miyazaki showed that MT1-
MMP could process APP outside the Aβ sequence [108]. In
this study, MT1-MMP activated by concanavalin A in the
HT1080 fibrosarcoma cell line was shown to cleave at the
­Asn579 and M­ et580 site of A
­ PP770 ­(VLAN579-M580ISEPR),
releasing a soluble truncated APP fragment lacking the
MMP-2 inhibitory domain (ISYGNDALMP). This deca-
peptide was previously reported in a study where MMP-2
was originally identified as a putative α-secretase capable
of hydrolizing the ­Lys16-Leu17 bond within the Aβ sequence
[109]. The decapeptide, known as APP-derived peptide
inhibitor (APP-IP), specifically inhibits MMP-2 with an
­IC50 value of 30 nM, well below the 2 µM for MT1-MMP
13

3174
and > 10 µM for MMP-3, -7 and -9. The APP-IP sequence,
spanning from amino acids 579–601 (βAPP770 numbering),
is present in sAPPα and sAPPβ. The authors concluded that
MT1-MMP processing of APP would be a way for the tan-
dem MMP-2/MT1-MMP to regulate ECM proteolysis [108].
Additional work on HEK293T cells demonstrated that MT1-,
MT3-, and MT5-MMP could release 5 major APP fragments
after being co-expressed with ­APP770 [110]. In this study,
the cleavage sites for MT3-MMP were identified by mass
spectrometry at positions ­Ala463-Met464, ­Asn579-Met580
­(VLAN579-M580ISEPR), ­His622-Ser623 and H ­ is685-Gln686. It
579 580
is noticeable that cleavage at A­ sn -Met by MT3-MMP
matches the MT1-MMP-mediated cleavage previously iden-
tified by Higashi and Miyazaki [108]. It is also interesting
to note that although ­His685-Gln686 cleavage is one residue
upstream of the α-cleavage site in the Aβ sequence, MT3-
MMP does not modify Aβ levels in HEK293T cells [110].
The authors suggested that MT5-MMP could have cleavage
profiles similar to those of MT1- and MT3-MMP, which
has been confirmed by a recent study showing that MT5-
MMP can effectively cleave the shorter neuronal isoform of
­APP696 at the ­VLAN504-M505ISEPR, also known as eta (η)
site [111]. According to this study, MT5-MMP (η-secretase)
generates a CTF fragment of ~ 30 kDa (CTF-30/η-CTF) that
can be further cleaved by α-secretase to produce a peptide
(Aη-α, for amyloid eta-alpha) of ~ 12 kDa, which impairs
LTP in cultured rat neurons. On the contrary, the concerted
action of η- and β-secretase generates the Aη-β peptide,
surprisingly lacking neurotoxicity. Together, these data
challenge the traditional view of α- and β-secretase as ben-
eficial and detrimental enzymes, respectively. Interestingly,
η-cleavage by MT5-MMP is strongly potentiated in the pres-
ence of BACE-1 inhibitors, raising concerns about possible
side effects mediated by the MMP in the case of therapeutic
inhibition of BACE-1. The putative Aη-α peptide was found
in the CSF of Alzheimer’s patients and healthy individuals,
but the concentrations did not differ between the two groups,
making it difficult for the moment to assess the importance
of Aη-α in AD pathology. Of note, despite that MT5- and
MT1-MMP cleave at the V ­ LAN504-M505ISEPR site, only
MT5-MMP and not MT1-MMP was identified in this study
as having η-secretase activity in vivo at 10 days postnatal
[111].
By the same time, our group tested the implication of
MT5-MMP in AD using a different approach; we crossed
transgenic 5xFAD mice carrying familial AD mutations in
human APP and Psen1 genes [112] with MT5-MMP knock-
out mice [113]. The resulting bigenic 5xFAD/MT5-MMP-/-
strain exhibits dramatic reductions of Aβ burden (e.g.,
plaques, oligomers, soluble Aβ40 and Aβ42) and C99 levels
in cortical and hippocampal regions [114]. The fall in Aβ/
C99 levels is concomitant with reduced glial reactivity and
reduced levels of IL-1β and TNF-α in different brain areas
13
S. Rivera et al.
[114, 115]. Functionally, 5xFAD mice exhibit impaired LTP
[116, 117] and impaired learning and memory [118–120].
Both deficits are reversed in 5xFAD/MT5-MMP-/- bigenic
mice, which show preservation of LTP and olfactory and
spatial learning and memory, compared to 5xFAD controls
[114, 115]. It is also important to note that the lack of MT5-
MMP strongly decreases the release of a soluble N-terminal
APP fragment of ~ 95 kDa (sAPP95), complementary of
the transmembrane CTF-30 fragment [114], supporting the
notion that APP is an in vivo substrate of MT5-MMP. In
addition to these in vivo data, MT5-MMP co-immunopre-
cipitates with APP following MT5-MMP overexpression in
HEK293 cells expressing App with the Swedish mutation
(HEKswe), resulting in the release of sAPP95 and increases
in Aβ40 levels [114, 115]. Although the precise molecular
mechanism behind MT5-MMP actions is still elusive, it is
known that the proteinase is internalized in the endosomal
system [121] and favours APP sorting in endosomes [115],
a major site of Aβ formation. In addition, it has been shown
that N2a Swedish cells release exosomes containing η-CTF
that can be uptaken by neurons [122]. Overall, MT5-MMP
could promote trafficking of APP or its metabolites (i.e.,
CTF-30/η-CTF) into intracellular organelles for more effi-
cient amyloidogenic processing by β- and γ-secretases. This
way of cooperative cleavage has been recently shown for
asparagine endopeptidase (δ-secretase), whose cleavage of
APP upstream the β-cleavage site favours subsequent pro-
cessing by β-secretase [123]. Not exclusively, it is also con-
ceivable that η-CTF could be used as an exosomal cargo for
intercellular propagation (see Fig. 1 for schematic represen-
tation of MT5-MMP interactions with APP).
The structurally close MT1-MMP shares about 60%
sequence homology with MT5-MMP. While MT5-MMP
is primarily expressed in the nervous system, MT1-MMP
is ubiquitously distributed in the organism, including the
brain. We found that MT1-MMP expression is upregulated
in the brains of 5xFAD mice at symptomatic stages of the
pathology and its overexpression in HEKswe cells stimulates
C99 and Aβ production [78]. Moreover, MT1-MMP inter-
acts with APP in HEKswe cells, and such interaction gener-
ates sAPP95 and the complementary transmembrane CTF-
30, eventually leading to twofold increase of Aβ40 levels
[124]. Consistent with its prominent β-secretase role, it was
shown that BACE-1 inhibition with C3 almost suppresses
basal Aβ production. Interestingly, such drastic effect of C3
is prevented in the presence of MT1-MMP, which restores
Aβ basal levels, suggesting that MT1-MMP may function
as a surrogate β-secretase upon BACE-1 inhibition [124].
The β-secretase-like activity of MT1-MMP may reveal
functional redundancies with BACE-1, which could be use-
ful for maintaining the physiological levels of Aβ in situa-
tions where, for example, BACE-1 would be therapeutically
inhibited. From these studies, it appears that MT5-MMP
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other…
Fig. 1  Schematic model summarizing the potential roles of MT1- and
MT5-MMP in APP  processing and the amyloidogenic pathway. 1:
Canonical amyloid precursor protein (APP) and MT-MMPs are tar-
geted from the trans-Golgi network (TGN) to the plasma membrane
or directly to the endosomal pathway. 2: On the plasma membrane,
MT-MMPs generate a soluble APP fragment of 95 kDa (sAPP95),
either alone or in concert with MMP-2, and the residual transmem-
brane fragment of 30 kDa (CTF-30/η-CTF). 3: Also at the membrane
level, APP can be processed by α-secretase through the canonical
pathway that generates sAPPα and the transmembrane α-CTF/C83.
In addition, the combined action of MT-MMPs and α-secretase could
generate a synaptotoxic peptide (Aη-α). 4: MT-MMPs could promote
the internalization of CTF-30/η-CTF or unprocessed APP in early
endosomes (5), where β-secretase generates sAPPβ, β-CTF/C99 or
Aη-β. β-secretase processing of APP may also occur in multivesicular
3175
bodies (MVB) (6), followed by γ-secretase cleavage (7) to generate
beta amyloid peptide (Aβ) and APP intracellular domain (AICD). The
latter may be also generated in the lysosomes (8) and translocated
into the nucleus (9). Aβ and sAPPβ can be degraded by lysosomes
(10) or released into the extracellular space (11). CTF-30/η-CTF
and Aβ can also be released in exosomes (12). Note that generation
of η-fragments has only been reported for MT5-MMP so far. The
contribution of MMP-2 to sAPP95 production has been described in
association with MT1-MMP, and it remains to be determined whether
this could also be the case for MT5-MMP. For the sake of simplicity,
the cartoon does not show late and recycling endosomes, the possible
location of γ-secretase on  the plasma membrane or APP trafficking
between the endosomal system and the TGN. This scheme includes
freely available objects from Servier Medical Art templates (https​://
smart​.servi​er.com)
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3176
and MT1-MMP behave differently in response to BACE-1
inhibition; while MT5-MMP would generate synaptotoxic
peptides (i.e., Aη-α) leveraging on increased APP bioavail-
ability for α-secretase, MT1-MMP would rather compensate
for a physiological deficiency in Aβ. Another interesting fea-
ture is that sAPP95 release by MT1-MMP partially involves
MMP-2 when activated by MT1-MMP. In the absence of
MT1-MMP, MMP-2 loses its ability to generate sAPP95,
indicating that MT1-MMP is the step-limiting enzyme
[124]. It remains to be elucidated whether MMP-2 can also
cleave at ­VLAN579-M580ISEPR, which would indicate the
existence of a consensus cleavage site for APP shared by
several MT-MMPs and MMP-2. These data highlight a new
function for MMP-2—in tandem with MT1-MMP—in addi-
tion to its Aβ-degrading properties, thus providing a new
example of the dual/multifunctional nature of MMPs.
Like MT5-MMP, MT1-MMP also favours endosomal
APP sorting [124]. Gaining insight into endocytosis and
recycling of MT-MMPs between the endosomal system and
the membrane may be essential to understand the patho-
physiological features of these enzymes. In this context, both
MT1-MMP [125] and APP [126] are internalized through a
clathrin-dependent mechanism that involves specific short
sequences of their cytoplasmic tails. MT5-MMP internali-
zation and recycling is mediated by interactions between
the last three residues at carboxyl terminus and Mint3, a
protein that contains two type III PDZ domains [121].
Mint3 has also been identified as an adaptor protein that
promotes the export of APP from the Golgi complex [127].
Together, these data may reflect interdependent trafficking
mechanisms between MT-MMPs and APP that enable func-
tional interactions eventually leading to C99/Aβ production
(summarized in Fig. 1).
Overall, MT-MMPs appear as new actors in AD patho-
genesis, with multiple influences on pathways where proteo-
lytic and non-proteolytic interactions with APP can coexist.
A better understanding of such interactions is needed to shed
light on the underlying pathogenic mechanisms.
Singular contributions of ADAMs to Alzheimer’s
disease
Although the importance of ADAMs in AD has long been
recognized for their contribution to α-secretase activity [128,
129], recent research extends their scope to mechanisms
other than those involving a direct cleavage of APP. For
instance, it has been shown that ADAM30 stimulates APP
sorting to lysosomes and its degradation via the activation
of cathepsin D [130]. It is also noteworthy that ADAM10
[131, 132] and ADAM17 [133] can shed the triggering
receptor expressed on myeloid cells 2 (TREM2), a protein
for which some genetic variants are linked to an increased
risk of AD (see [134] for review). Mechanistically, lowering
13
S. Rivera et al.
cell surface TREM2 results in reduction of microglia phago-
cytic activity, thereby possibly contributing to Aβ accumu-
lation [131]. Similarly, the shedding of LRP-1 by different
ADAMs (e.g., ADAM12) [99] might affect the ability of
this receptor to promote endocytic-mediated clearance of
Aβ. Finally, ADAMs could also contribute to the control of
chronic inflammation by regulating cytokine activity. This
could be the case of ADAM17, which sheds membrane-
bound TNF-α and releases its soluble form [135]. Increasing
experimental evidence suggests that TNF-α contributes to
AD pathogenesis and TNF-α inhibitors, some of which are
in clinical trials, may improve the pathological and cognitive
outcome (reviewed in [136]).
TIMPs in Alzheimer’s disease
Along with the accumulation of data demonstrating the
involvement of metalloproteinases in neurodegenerative
processes , the interest in their inhibitors has increased in
parallel. The list of endogenous MMP inhibitors and their
physiological implications in the nervous system is rather
extensive and has already been examined elsewhere [3]. We
will focus on TIMPs in the context of this review.
Early work reported the presence of TIMP-1 in neu-
ritic lesions of AD and colocalization with APP, as well as
with abnormally phosphorylated and truncated tau [137].
Since then, numerous attempts to describe a clear profile
of expression for TIMPs have been undertaken with even-
tually somehow discordant results. It has been shown that
TIMP-1 and TIMP-2 levels remain stable when comparing
patients suffering from AD or mild cognitive impairment
(MCI) with non-demented controls [92]. While plasma lev-
els of MMP-9 were higher in AD, PD and ALS patients
compared to healthy individuals, no changes in TIMP-1
and TIMP-2 levels were observed in the same work [138].
A pilot study on a small cohort of AD patients reported
moderately elevated levels of TIMP-1 in plasma [139].
The comparison of different types of dementia reveals that
plasma levels of TIMP-1 and TIMP-2 respectively decrease
in vascular and frontotemporal dementia, compared to
AD and MCI [95]. However, TIMP-2 levels are increased
in the CSF of Alzheimer patients [138]. Another study
showed increased levels of TIMP-1 in bigenic APPSwDI/
NOS2-/- mice compared to APPSwDI controls, along with
decreased MMP activity and increased Aβ levels, suggest-
ing that TIMP-1 could negatively influence the pathological
outcome as a consequence of lowered nitric oxide produc-
tion [140]. It has been proposed that the concentration of
TIMP-1 in the CSF is a distinctive biomarker to differentiate
AD patients from those with subcortical vascular disease,
the latter having higher levels than the former [107]. In the
same vein, Duits and collaborators reported decreased lev-
els of TIMP-1 and TIMP-2 in the CSF of AD patients with
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other…
cerebral microbleeds, arguing for an imbalance in favour of
MMP proteolytic activity, which could eventually contribute
to the generation of such lesions  [141].
TIMP-1 was found to be secreted by neurons in response
to MMP-9 release by mixed neuron/astrocyte cultures when
exposed to neurotoxic Aβ25-35, and to stimulate astrocyte
proliferation [142], in agreement with our previous work
[143]. Coincident with gliosis, TIMP-1 mRNA expres-
sion is strongly upregulated at early stages (between 4 and
6 months) of the pathology in the brain of 5xFAD mice,
whereas TIMP-2 and TIMP-3 mRNA levels show only mod-
erate changes during the same period [78]. It remains to be
assessed  whether TIMP-1-mediated gliosis represents a
self-defence mechanism to eliminate Aβ and/or a conse-
quence of chronic inflammation. Increased levels of TIMP-
1, along with the absence of MMP-9, have been observed
in microvessels of AD compared to non-demented controls.
The authors correlated this observation with the ability of
thrombin to induce TIMP-1 expression in cultured brain
endothelial cells. Altogether, these data suggest that changes
in angiogenesis in AD brains may involve the modulation of
the MMP-9/TIMP-1 balance [144].
Although not directly associated with AD, TIMP-2
mRNA and protein have been proposed as biomarkers of
aging in the heart and cerebellum [145]. These results are
particularly significant in the context of recent findings from
Wyss–Coray’s group showing that TIMP-2 is an essential
anti-aging factor as it promotes neuroplasticity, including
LTP and hippocampal-dependent cognition. These conclu-
sions were drawn after elegant parabiotic experiments in
which plasma from young donor mice enriched with TIMP-2
compensated for cognitive deficits in elderly recipient mice,
evoking the effect of an “elixir of eternal youth” [146]. With
aging being the main risk factor for AD, TIMP-2, as a reju-
venating factor, could certainly play a role in the prevention
of AD and other neurodegenerative diseases.
TIMP-3 inhibits APP cleavage by α-secretases ADAM10
and ADAM17, resulting in increased levels of C99 and Aβ,
probably due to increased cleavage of APP by β-secretase
[147]. The proposed mechanism implies that α-secretase
inhibition by TIMP-3 could stimulate APP trafficking to
endosomes, where β- and γ-secretases convert APP to Aβ.
Consitent with this hypothesis, TIMP-3 levels are upregu-
lated in brains from both AD patients and transgenic AD
mice [147]. In addition, TIMP-3 expression is correlated
with NFT in AD patients compared to non-demented indi-
viduals [148].
TIMP-4 has been less studied in neurodegenerative dis-
eases than the other three TIMPs. Only one study reports
that plasma levels of TIMP-4 are higher in AD patients than
in healthy controls and TIMP-4 levels positively correlate
with the severity of the disease [149]. While we are still
waiting for clear evidence of TIMP-4 functions in the CNS,
3177
its inhibitory potential on MMPs suggests that it could con-
tribute to modulate the progression of neurodegenerative
diseases.
Parkinson’s disease
PD is the second most common neurodegenerative disorder
after AD,  characterised by motor symptoms, including rest
tremor, bradykinesia, muscle stiffness, impaired posture and
balance, and loss of automatic movement. Motor impair-
ment is associated with selective loss of dopaminergic neu-
rons in the substantia nigra and the degeneration of their
striatal projections. Although PD is an incurable disease,
a number of drugs and surgical interventions have shown
to be effective and significantly improve symptoms for a
limited period of time. A major feature of PD is the pres-
ence of fibrillar intracellular aggregates called Lewy bodies
(LBs) in different brain areas. LBs are mainly composed
of α-synuclein (α-Syn), a presynaptic protein of 140 amino
acids for which three missense mutations (A30P, E46K and
A53T) as well as wild-type gene multiplications, have been
associated with familial forms of PD [150–154]. α-Syn
aggregation has also been reported in sporadic forms of PD
of unknown etiology, which constitute the majority of cases
[155, 156]. It should be noted that α-Syn neuronal aggre-
gates released into the extracellular space can be internalized
by other neurons, reminiscent of a prion-like mechanism
that can promote PD progression through the self-propa-
gation of α-Syn [157]. In addition to α-Syn, ninety other
molecules have been identified in LBs, including parkin,
tau, leucine-rich repeat kinase 2 (LRRK2), DJ-1 and APP
[158]. Even though a clear correlation exists between PD
and the presence of LBs, the causal role of these aggregates
has been questioned by recent studies in which early signs of
neuronal dysfunction/death in the substantia nigra precede
LBs formation [159]. In this context, other authors have sug-
gested that α-Syn oligomers and protofibrils are true toxic
assemblies as opposed to fibrillar structures contained in
LBs, which would rather convey neuroprotective roles [158,
160–162]. Alternatively, there is also experimental evidence
that truncated forms of α-Syn contribute to PD and dementia
with Lewy bodies (DLB) pathology. Early work reported
the presence of truncated α-Syn in isolated LBs from DLB
brains [163] and in transgenic mice harbouring the A53T
familial mutation [164]. Subsequently, 3 other C-terminal
truncated major peptides (residues 1-78, 1-91 and 1-93)
were identified, with the particularity that they were more
abundant after digestion of A53T α-Syn compared to wild-
type  [165]. When the 1-93 peptide was overexpressed in
the mouse substantia nigra it selectively killed dopaminer-
gic neurons independently of LB-like formation. Crowther
and colleagues demonstrated in vitro the ability of these
13

3178
truncated α-Syn forms to aggregate into filaments [166],
while other authors found that stable expression of C-ter-
minal truncated α-Syn increases neuroblastoma cell vulner-
ability to oxidative stress [167]. These data clearly indicate
that α-Syn fragments contribute to PD and DLB pathogen-
esis, and several reports involve MMPs in α-Syn truncation.
One study showed that, in this order of efficacy, MMP-3,
MT1-MMP, MMP-2, MMP-1 and MMP-9 cleaved recom-
binant α-Syn in vitro [168], a cleavage that was confirmed
in another study for MMP-1, MMP-3 and MMP-9 [169].
α-Syn fragments generated by MMP-3 are prone to form
amyloidogenic aggregates that exhibit higher cytotoxicity
compared to intact α-Syn. Further support for a pathogenic
role of MMP-3 in PD comes from reports showing elevated
expression of the enzyme in dopaminergic neurons of the
substantia nigra in a rat model of PD induced by 6-hydroxy-
dopamine (6-OHDA) [168], as well as in the brains of PD
patients [165]. In addition, in another PD model induced by
the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyr-
idine (MPTP), the production of reactive oxygen species
and the degeneration of dopamine neurons are attenuated in
MMP-3-deficient mice [170], these effects being associated
with the prevention of BBB disruption and the improvement
of locomotor activity [171]. Along this line, intracellular
activation of MMP-3 triggers neuronal apoptosis [172] and
the subsequent release of active MMP-3, which stimulates
the production of inflammatory cytokines by neighbouring
microglia and eventually the exacerbation of dopaminergic
neuron death [173]. Cultured microglia undergoes activa-
tion in response to α-Syn by a mechanism that involves the
upregulation of MMP expression (i.e., MMP-1, -3, -8 and
-9), and the consequent proteolytic activation of protease-
activated receptor-1 [174]. Under these conditions, the inhi-
bition of MMP-8 effectively reduces the levels of reactive
oxygen species and inflammatory mediators such as TNF-α
and IL-1β. MMP-3 implication in PD pathology has also
been related to its ability to cleave DJ-1. The latter is a pro-
tein deglycase with protective antioxidant properties that
mediates pleiotropic cellular responses, and whose mutation
is associated with autosomal recessive early-onset PD [175].
MMP-3-mediated cleavage of DJ-1 impairs its antioxidant
function in cultured dopamine-producing CATH.a cells upon
oxidative stress [176]. The same study provided ground for
in vivo cleavage, as the decrease in DJ-1 content observed
after MPTP treatment was prevented in MMP-3 knockout
mice. Interestingly, one of the DJ-1 mutations (L166P) pre-
vents its dimerization and causes its proteolytic digestion
by the proteasome [177, 178]. Also noteworthy, the L1669
mutation abrogates the anti-aggregation properties of wild-
type DJ-1 with respect to α-Syn [179]. From these data, it
follows that MMP-3 processing of DJ-1 could harm its anti-
oxidant and anti-α-Syn aggregation properties. In addition,
DJ-1 can be cleaved effectively by MT1-MMP as well as by
13
S. Rivera et al.
MMP-1, -2, -8 and -9 [180], indicating that DJ-1 is a sub-
strate of several MMPs and that these interactions may have
pathophysiological significance in PD.
The functional and regulatory interplay between various
MMPs and PD markers further strengthens the implica-
tion of MMPs in PD pathogenesis. Thus, α-Syn stimulates
the expression of MMP-9 by cultured microglia and astro-
cytes [181]. Moreover, α-Syn promotes the expression of
MT1-MMP and cell adhesion molecule CD44 in microglial
cells. Shedding of CD44 by MT1-MMP facilitates micro-
glia detachment from the ECM and promotes its migra-
tion in vitro [182]. Accordingly, siRNA-mediated silenc-
ing of MT1-MMP dramatically decreases the migration
of the microglial cell line BV-2 when transplanted in the
injured substantia nigra of 6-OHDA treated mice, suggest-
ing that MT1-MMP stimulates microglia recruitment into
injured brain areas and thus accelerates the degenerative
process [182]. Mutations in the LRRK2 gene are the most
common cause of autosomal dominantly inherited PD [183,
184]. One study on microglia and leukocytes from LRRK2
mutant mice showed that increased levels of inflamma-
tory mediators and decreased levels of anti-inflammatory
progranulin (PGRN) were associated with increased and
decreased levels of MMP-2 and MMP-9, respectively. Also
interesting, hippocampal neurons of LRRK2 mutant mice
show high levels of MMP-12 [185], an enzyme that cleaves
microglial PGRN, thereby possibly interfering with its anti-
inflammatory properties [186]. Together, these data are par-
ticularly sound because microglia is a critical regulator of
the inflammatory process that accompanies PD pathogenesis
(reviewed in [187]).
In order to implement cell-based neuroprotective strat-
egies against PD, conditioned media from cultured mes-
enchymal stem cells (MSC) have been used to disaggre-
gate preformed α-Syn fibrils in vitro, with the consequent
increase in cell viability. Conditioned media of cells treated
with MMP-2 siRNA prevented the beneficial effects of
normal conditioned media, suggesting that MMP-2 is one
of the soluble factors that confer neuroprotection [188].
In line with these observations, reduced levels of MMP-2
in MPTP-treated mice can be restored by the inoculation
of MSC. In addition, injection of MMP-2 in the brain of
mice pre-inoculated with α-Syn degrades extracellu-
lar α-Syn aggregates and oligomers [188]. Also consist-
ent with these data, MMP-2 levels were decreased in the
substantia nigra of post mortem PD brains, while those of
TIMP-1 were increased [189]. Whether the MMP/TIMP
ratio may be used as a marker of PD progression is still
unclear, despite studies associating reduced TIMP-2 levels
and increased vulnerability of neuroblastoma cells to MPTP
or 6-OHDA, which is consistent with TIMP-2 preventing
the effects of these neurotoxins [190]. It appears, therefore,
that different MMPs display opposite actions in PD; while
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other…
MMP-3 cleavage of α-Syn could promote its aggregation
into neurotoxic fibrils, MMP-2 could rather degrade them,
thus providing neuroprotection. Therefore, the distinction
between both MMPs should be considered in prospective
anti-PD therapies with MMPs as potential targets in PD. In
this line, it has been shown that the inhibition of MMP-8
in the ­LRRK2G2019S mouse model reduces the levels of
inflammatory mediators and improves locomotor activity
during systemic inflammatory LPS challenge [191]. Like-
wise, hydroxamate-based MMP inhibitor Ro28-2653, which
targets MMP-2, -9 and MT1-MMP, significantly reduces
neuronal loss and MMP-9 levels in the substantia nigra of
MPTP-treated mice [192].
There are no reports yet linking ADAM function to PD.
However, since the contribution of reactive microglia to
pathology is increasingly supported by experimental data,
it would be justified to explore in this context the modulation
by ADAMs of proteins involved in microglial function, such
as TREM2. Of note, some authors have reported association
between TREM2 variants and increased risk of PD, although
the data are not conclusive for the moment [134].
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a rare rapidly pro-
gressive neurodegenerative disease that selectively affects
motor neurons in the brain, brainstem and spinal cord, lead-
ing to severe disability, muscle atrophy, and also cognitive
deficits in about 40% of ALS patients. Poor prognosis is
a distinctive clinical feature and life expectancy after the
diagnosis is less than 20 months in 50% of patients, who
often die from ventilatory failure (see for review [193]). Cur-
rently, there are no drugs that can cure or prevent ALS and
the rapid course of the disease, as well as the lack of reliable
biomarkers, make therapeutic strategies particularly chal-
lenging. As with many other degenerative diseases, aging is
a major risk factor, with a rapid increase in prevalence after
age 55 [193]. While the majority of patients have sporadic
ALS of unknown multifactorial origin, genetically linked
ALS accounts for between 5 and 10% of cases. Deleterious
genetic mutations affect genes coding for proteins implicated
in RNA processing, and protein transport and clearance, like
C9orf72, SOD1, TDP-43 and FUS (reviewed in [194]).
The pathogenesis of ALS is likely the result of a combi-
nation of genetic and environmental factors that may influ-
ence key biological processes such as excitatory/inhibitory
neurotransmitter balance, BBB integrity, protein folding,
oxidative stress or neuroinflammation. All of these events
are commonly linked with MMP activity, and a number of
evidences discussed below support the role of MMPs in the
disease.
3179
Many studies on ALS have used transgenic mice express-
ing ­C u 2+/Zn 2+ superoxide dismutase (SOD1) carrying
the G93A familial mutation (­ SOD1G93A). In these mice,
the involvement of MMP-9 in ALS pathogenesis is still
under debate because different laboratories have reported
conflicting data. One study shows that MMP-9 deletion
in ­SOD1G93A mice accelerates motor neuron disease and
increases cell death [195], whereas another study reports
decreased neuron loss and greater survival in MMP-9 knock-
out mice in correlation with decreased TNF-α and FasL
immunostaining [196]. Selective expression of MMP-9 in
fast-fatigable motor neurons, which are highly vulnerable in
­SOD1G93A mice compared to the fast-fatigue resistant and
slow motor neuron subtypes, is concomitant with the activa-
tion of the unfolded protein response and endoplasmic retic-
ulum stress mark characteristic of early pathological stages
of ­SOD1G93A. Genetic deletion of MMP-9 in these mice, as
well as pharmacological inhibition or viral gene therapy,
delays muscle denervation [197]. In an attempt to interpret
selective motor neuron vulnerability, it has been shown that
osteopontin, an ECM protein, is selectively expressed in
fast-fatigue resistant and slow motor neurons, and stimulates
late expression of MMP-9 in these neuronal subtypes, which
could contribute to the second wave of degeneration in ALS
by a mechanism controlled by MMP-9 [198]. Another study
showed that early administration of MMP inhibitor Ro28-
2653 increases the survival of S ­ OD1G93A mice [199], sug-
gesting a powerful detrimental activity of MMPs in ALS.
in vitro studies further support the possible contribution of
MMP-9 to ALS, as MMP-9 inhibition with glycoursodeoxy-
­ OD1G93A prevents cell degen-
cholic acid in a cell model of S
eration [200]. Although these data suggest that MMP-9 can
be a candidate for therapeutic intervention in ALS, caution
is required; indeed, in a sporadic model of ALS using rNLS8
mice, MMP-9 knockdown leads to the preservation of motor
neurons and muscle function, even if in the long run the
reduction of MMP-9 results in premature death of a subset of
rNLS8 mice [201]. It is then possible that targeting MMP-9
outside the neuromotor system may cause adverse effects
due to the inhibition of more general physiological processes
controlled by this MMP. In addition, MMP-9 could also be
considered as an early biomarker of the disease. MMP-9
(and also MMP-2) levels measured by gelatin zymography
were found to increase in the serum of ­SOD1G93A mice at
the beginning of the symptomatic phases of the pathology,
as opposed to significantly lower levels observed during the
pre-symptomatic and late-end stages [202].
Beyond a neurocentric interpretation of ALS patho-
genesis, astrocytes could also play a deleterious role,
thereby justifying attempts to replace diseased astrocytes
by healthy astrocytes. Izrael and colleagues intrathecally
injected astrocytes derived from human embryonic stem
cells into transgenic ­SOD1G93A mice and rats, and observed
13

3180
an improvement of motor performance and delayed disease
onset linked to astrocytic secretion of TIMP-1 and TIMP-2
[203]. On the contrary, a positive correlation has been put
forward between TIMP-3 levels and neurodegeneration.
Degenerating neurons of S ­ OD1 G93A mice exhibit aug-
mented TIMP-3 levels in parallel with increased interactions
between Fas and Fas-associated protein with death domain
(FADD). Mechanistically, TIMP-3 inhibition of FADD
cleavage by MMP-3 would stabilize Fas–FADD interactions,
thereby promoting Fas-mediated apoptosis [204].
Few studies have been conducted in patients to explore
possible changes in MMP content. Pioneer work in CNS tis-
sue from ALS patients localized increased immunostaining
of MMP-2 in astrocytes and MMP-9 in pyramidal neurons
of the motor cortex and in spinal motor neurons [205]. In
addition, one study reported increased levels of MMP-9 in
plasma of ALS patients but not in CSF [206], while another
study also reported an increase in MMP-9 levels in CSF
[207]. It has been shown by ELISA assay that the concen-
tration of MT1-MMP, MMP-2 and TIMP-1 increases in the
CSF of ALS patients compared to healthy controls [208],
thus confirming previous work showing increased TIMP-1
levels in the CSF as well [138].
There is scarce information on ADAMs in ALS. One
study described enhanced secretion of TNF-α by microglia
from ­SOD1G93A, ­SOD1L8Q, or S ­ OD1G10V mutants upon
shedding by ADAM10 and ADAM17, thereby contribut-
ing to microglia inflammatory response [209]. In the same
vein, it was shown that iron accumulation in ventral motor
neurons of S ­ OD1G93A mice induced oxidative stress and
the secretion of TNF-α mediated by increased ADAM17
activity [210]. It has been suggested that the reduction in
ADAMTS-4 observed in the spinal cord of S ­ OD1G93A mice
may be an adaptive mechanism to counteract the poten-
tial neurotoxic effect of this metalloproteinase [211]. The
authors reached this conclusion after observing significant
motor neuron death following the injection of recombinant
ADAMTS-4 in the spinal cord of S ­ OD1G93A mice. Collec-
tively, different ADAMs could, therefore, contribute to the
degenerative process that takes place in ALS.
Huntington’s disease
HD (also known as Huntington’s chorea) is the most fre-
quent among inherited neurodegenerative polyglutamine dis-
orders. It is still an incurable disease that causes changes in
mood and mental abilities, as well as deficits in motor coor-
dination and ultimately dementia. HD is not properly speak-
ing an aging-related disease since symptoms may appear
at the age of 40 or even earlier. The cause of the disease
lies on the mutation of the gene coding for huntingtin (Htt),
which presents an expanded CAG triplet repeat in exon 1
13
S. Rivera et al.
that encodes a chain of polyglutamine (polyQ) residues close
to the N-terminus of Htt. This results in the aggregation of
Htt in the nucleus and cytoplasm of neurons and the conse-
quent cell demise that affects mainly the striatum and cortex
[212–214]. The underlying neurotoxic mechanism is still
elusive, but several lines of evidence point to Htt proteolysis
by caspases and calpains, which releases N-terminal small
fragments thought to be particularly toxic [215–217]. More
recently, Miller and collaborators expanded the repertoire of
proteinases involved in this process to MMPs [218]. They
screened 514 siRNA targeting all the proteinases encoded
by the human genome to determine those whose inhibi-
tion would reduce Htt processing, and more precisely the
production of small N-terminal fragments. Among 11 con-
firmed proteinases, they found MMP-10, MT1-MMP and
MMP-23B. They confirmed the upregulation of MMP-10
and MT1-MMP expression in striatal H ­ dh111Q/111Q cells as
7Q/7Q
compared to ­Hdh cells, and established a good correla-
tion between the knockdown of these MMPs and a signifi-
cant reduction of caspase activation in ­Hdh111Q/111Q cells.
In the same study it was shown that TIMP-1 and TIMP-3
inhibited Htt cytotoxicity in ­Hdh111Q/111Q cells. Moreover,
striatal MMP activity was also increased in Htt YAC128
(glutamine repeat expansion model) and R/62 (N-terminal
fragment model) mouse models of HD. While MT1-MMP
and MMP-2 do not directly cleave Htt, MMP-10 generates
a N-terminal fragment of 48 kDa after cleavage at residue
402, very close to the N-terminus. Importantly, H ­ dh111Q/111Q
cell death was prevented upon knockdown of MMP-10. Fur-
ther work from the same laboratory confirmed significant
alterations of MMPs expression in induced pluripotent stem
cell-derived neural stem cells from HD patients (HD-NSCs)
with an expanded CAG repeat, compared to the isogenic
corrected control [219]. The study shows that the expres-
sion of MMP-3 and -10 increases in HD-NSCs compared
to control NSCs, in contrast with the decrease observed
in MT1-MMP, TIMP-1 and TIMP-2. TIMP-1 levels were
restored by TGF-β treatment, in pace with reduced neurotox-
icity of Htt, suggesting overall a beneficial effect of TIMP-
1-mediated inhibition of Htt proteolysis by MMP-3 and -10
[219]. However, this idea is questionable, as other authors
have reported increased levels of TIMP-1 and -2 in the CSF
of HD patients [138].
MMP-9 levels are increased in post mortem tissues of
HD patients, as well as the content of pro-inflammatory
mediators MCP-1, IL-6, IL-8 and the anti-inflammatory
IL-10 [220]. Likewise, plasma MMP-9 and IL-6 levels are
higher in HD patients compared to healthy controls and this
is also observed in R6/2 HD mice compared to wild-type
littermates [221]. Moreover, MMP-3 and MMP-9 levels
increase in CSF from HD patients in correlation with dis-
ease severity [222]. The same authors showed that cultured
microglia from YAC128 mice (transgenic mouse model
Metalloproteinases and their tissue inhibitors in Alzheimer’s disease and other… 3181

with a 128-glutamine stretch) exhibits increased secretion
of cytokines upon stimulation with MMP-3, an activator
of microglia. Interestingly, the pro-inflammatory effect of
MMP-3 is equivalent to that caused by LPS treatment, link-
ing the action of MMPs in HD to their pro-inflammatory
properties. Seemingly, in a rat model of HD induced by
intraperitoneal administration of a natural toxin, 3-Nitro-
propionic acid, MMP-9 expression and gelatinolytic activity
are upregulated in injured striatal blood vessels, suggesting
the possible implication of MMP-9 in BBB disruption in
HD. Noticeably, MMP-9 expression has been reported to be
upregulated in subsets of astrocytes and microglial cells in
the vicinity of lesions [223]. In contrast with the aforemen-
tioned studies, other authors reported recently in HD patients
no changes in CSF MMP-9 levels and the lack of neuroin-
flammation at premanifest stages of the pathology [224].
With regard to ADAMs, one study reports the physiologi-
cal interaction between ADAM10 and Htt during neurulation
[225]. The authors found that Htt inhibits N-cadherin shed-
ding by ADAM10, which promotes neurulation and rosette
formation. They also found that ADAM10 activity increased
in the Htt-deficient adult brain, suggesting a role for Htt in
synapse plasticity and remodelling. The question arises as
to whether deficient regulation of ADAM10/N-cadherin in
HD brains with dysfunctional Htt could possibly contribute
to the disease.
Concluding remarks and perspectives
The traditional view of metalloproteinases as merely non-
specific degrading enzymes is definitely obsolete. Their
implications in homeostatic or detrimental pathways in
many neurodegenerative diseases mobilize finely tuned
proteolytic interactions with substrates and the generation
of biologically active cleavage products. A plethora of sub-
strates has been identified and we can anticipate that their
number will grow in the coming years in the light of new
high-throughput proteomic techniques. Table 1 summarizes,

Table 1  Substrates that undergo direct or indirect cleavage under the influence of metalloproteinase actions
Alzheimer’s disease Parkinson’s disease Amyotrophic lateral sclerosis Huntington’s disease

MMP-1 – α-Syn [168, 169] – –

DJ-1 [180]
MMP-2 APP [109] α-Syn [168, 169] – Htt [218, 219]
Aβ [60, 61, 78, 82] DJ-1 [180]
tau [105]
MMP-3 Aβ [63] α-Syn [168, 169] FADD [204] –
tau [106] DJ-1 [176]
gelsolin [98]
MMP-7 Aβ [64] – – –
MMP-8 – DJ-1 [180] – –
MMP-9 APP [58, 61] α-Syn [168, 169] – –
Aβ [57, 59, 60, 70] DJ-1 [180]
tau [106]
claudin-5 [69]
RAGE [102, 103]
MMP-10 – – – Htt [218, 219]
MMP-12 – PGRN [186] – –
MMP-14 APP [78, 108–110, 124] α-Syn [168] – Htt [218, 219]
(MT1-MMP) Aβ [65] DJ-1 [180]
LRP-1 [99] CD44 [182]
MMP-16 APP [110] – – –
(MT3-MMP)
MMP-24 APP [110, 111, 114] – – –
(MT5-MMP)
ADAM10 APP [41, 42, 45] – TNF-α [209] N-cadherin [225]
LRP-1 [99]
RAGE [101, 102]
TREM2 [131, 132]
ADAM12 LRP-1 [99] – – –
ADAM17 APP [43] – TNF-α [209, 210] –
LRP-1 [99]
TREM2 [133]

13

3182
in a non-exhaustive manner, some of principal substrates
that have been cited in this review.
In some cases, metalloproteinases have a dual effect, as
it is the case for MT1-MMP in AD experimental models
by degrading Aβ and also contributing to its formation.
Likewise, α-secretases (e.g., ADAM10) may generate neu-
roprotective sAPPα and give rise to synaptotoxic C-terminal
fragments in synergy with MT5-MMP. We are witnessing
the expansion of APP processing beyond prototypical con-
trol by canonical secretases. In this scenario, MT-MMPs
appear to play an important role in the generation of new
truncated APP fragments, whose functions are still poorly
understood. Similar challenges arise when considering the
physiological and pathological roles of breakdown products
resulting from the metalloproteinase-mediated process-
ing of tau, α-Syn or Htt in AD, PD or HD, respectively.
Although proteolysis is clearly the main functional char-
acteristic of metalloproteinases, the field now opens up to
study proteolysis-independent protein–protein interactions,
such as those reported for ADAM30, which bring to light
new ways in which metalloproteinases can influence disease
outcomes. Therefore, it is plausible that new strategies will
emerge based on the modulation non-proteolytic interactions
between metalloproteinases and partner proteins. In addi-
tion, this could offer alternatives to targeting the proteolytic
activity of metalloproteinases, which often suffers from the
lack of specificity due to highly conserved catalytic domains
between family members.
Inflammation is a common event in neurodegenerative
diseases and many metalloproteinases are produced by
brain and peripheral immune cells. Gaining insight into
the disease will also require a better understanding of how
the metalloproteinases released by these cells contribute to
pathology in a given spatio-temporal context and/or how
metalloproteinases can activate/inactivate immune cells by
controlling the cleavage of key receptors and cytokines (e.g.,
TREM2, TNF-α, IL-1β, etc).
From all the above, it appears that the study of metal-
loproteinases warrants a more global approach in which we
can learn from their conserved functions as well as their
specificities. These concepts should inspire future research
on neurodegenerative diseases, where a thorough knowledge
of biological processes should pave the way for exciting dis-
coveries that will help to design more effective diagnostic
and therapeutic strategies.
Acknowledgements  This work was supported by funding from the
CNRS and Aix-Marseille Université and by public grants overseen
by the French National Research Agency (ANR), MAD5 to SR,
and PREVENTAD to MK, as part of the second “Investissements
d’Avernir” program. The work was also supported by the DHUNE
Centre of Excellence and grants from CoEN, “Fondation Plan Alz-
heimer”, France Alzheimer and Vaincre l’Alzheimer to SR. KB was
granted a research associate fellowship (Management of Talents) by
13
S. Rivera et al.
the Initiative d’Excellence of Aix-Marseille University - A*MIDEX,
a French “Investissements d’Avenir” programme.
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