See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/313426187

Exploration of Various Proteins for the Treatment of Alzheimer's Disease

Article  in  Current Drug Metabolism · February 2017

DOI: 10.2174/1389200218666170203110135

CITATIONS READS
10 127

4 authors, including:

Badar ul Islam Syed Kashif Zaidi

Aligarh Muslim University Center of Excellence In Genomic Medicine Research-KAAU
14 PUBLICATIONS   241 CITATIONS    84 PUBLICATIONS   1,985 CITATIONS   

SEE PROFILE SEE PROFILE

Shams Tabrez
King Abdulaziz University
177 PUBLICATIONS   4,777 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Call for review articles for SI of Medicinal Chemistry View project

Call for submission of your manuscripts to our special issue: "Synopsis on Antimicrobials Challenges—From Dentistry to Environmental Visions" View project

All content following this page was uploaded by Shams Tabrez on 10 April 2018.

The user has requested enhancement of the downloaded file.

 808 Send Orders for Reprints to reprints@benthamscience.ae

Current Drug Metabolism, 2017, 18, 808-813

REVIEW
ARTICLE
ISSN: 1389-2002
eISSN: 1875-5453

Current
Drug
Metabolism
Impact
Factor:
2.659

Exploration of Various Proteins for the Treatment of Alzheimer’s Disease The international

journal for timely

in-depth reviews

on Drug Metabolism

BENTHAM
SCIENCE

Badar ul Islam1, Syed Kashif Zaidi2, Mohammad Amjad Kamal3,4 and Shams Tabrez3,*

1
Department of Biochemistry, J. N. Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh 202002, India; 2 Cen-
ter of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia; 3King Fahd Medical Re-
search Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia; 4 Enzymoics, 7 Peterlee Place, Hebersham, NSW, Australia

ARTICLE HISTORY
Received: September 12, 2016
Abstract: Background: Alzheimer’s disease (AD) is an irreversible multifaceted neurodegenerative disorder that
gradually degrades neuronal cells. It is the most frequent cause of memory loss and dementia in elderly individuals
worldwide. The extracellular deposition of beta amyloid (A), intracellular neurofibrillary tangles (NFTs) retention,
neuronal decline and neurotransmitter system derangement are the patho-physiological marker of this devastated
disease.

tio y
Revised: October 06, 2016 Objective: In view of limited treatment option and their success rate, there is an urgent need to explore the vast array
Accepted: November 11, 2016
of proteomes for the management of AD. These proteins could be therapeutically targeted to prevent the progression

bu nl
DOI: of this disease. In the present review, we tried to uncover several proteins that could be exploited in AD therapeutics.

n
10.2174/1389200218666170203110135
Conclusion: Based on our article, we conclude that proteome based AD treatment needs more refinements and

tri O
approaches to achieve the desired success rate.
Keywords: Alzheimer’s disease, amyloid beta, amyloid precursor protein, apolipoprotein, tau, therapeutics.
is e
1. INTRODUCTION different proteins that could be therapeutically targeted to decipher
s
A multifactorial neurodegenerative disease (Alzheimer’s) the mysteries of AD puzzle in clinical perspectives.
rD U

gained interest among researchers for the past several years due to
1.1. Amyloid Precursor Protein (APP)
its worldwide etiology [1]. It is the most common form of dementia
Current Drug Metabolism

characterized by neuronal dysfunction and apoptosis that results in Amyloid precursor protein is a type I transmembrane protein. It is
Fo al

memory decline and impaired cognitive functions. About 36 million produced in the endoplasmic reticulum (ER) as an antecedent for A
people across the globe are affected by this disorder and this num- and other peptides [15]. Post-translation, it is extensively altered via
ber is expected to reach up to 114 million by 2050 [2, 3]. AD is glycosylation followed by phosphorylation at some residues inside
ot on

categorized into early onset or familial (1-6%) and sporadic (>90%) the cytoplasmic domain [16]. In this domain the interaction with vari-
[4]. Its multifaceted pathophysiology includes enhanced retention ous cytoplasmic proteins took place which aids in transport to differ-
of amyloid beta (A) plaque around neuronal cells and neurofibril- ent locations [17]. In amyloidogenic pathway, APP is cleaved by -
N rs

lary tangles formed by hyper-phosphorylated tau-related microtu- and -secretase enzymes whereas in non-amyloidogenic pathway,
bule inside cells [5]. Some other disturbed mechanisms like calcium cleavage is carried out by - and -secretase enzymes (Fig. 1). The
Pe

release, persistent oxidative imbalance, mitochondrial and mitotic
dysfunction, hormonal disparity and inflammation are also believed
to participate in AD pathogenesis. The proteasome system is the
main clearance machinery for hyper-phosphorylated tau protein
which gets blocked by A oligomers and plaques [6]. As a result,
intracellular Ca2+ concentration gets disturbed which activates vari-
ous inflammatory cascades, thereby promote neuronal dysfunction
[7, 8]. Different hypotheses for AD pathogenesis have been put
forwarded in literature which includes amyloid [9], glutamate-
mediated or glutamatergic [10], oxidative imbalance [11], inflam-
matory-mediated [12], acetylcholine-mediated or cholinergic [13]
and metal-based [14].
The complex mechanisms involved in AD progression restrain
the actual beneficial effect associated with any anti-Alzheimer drug.
Till date, memantine, and four other cholinesterase inhibitors are
approved by the US-FDA (Food and Drug Administration) for AD
management. However, these drugs were unable to divert the route
of the disease rather they just provide symptomatic effects. There-
fore, the need of the hour is to find out novel and sophisticated
therapeutic alternatives. In the present review, we focus on the
*Address correspondence to this author at the King Fahd Medical Research
Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi
Arabia; E-mail: shamstabrez1@gmail.com
soluble APP fragment has been noted for neuroprotective features
and signaling properties [18, 19]. Immunocytochemical studies re-
vealed the locations of APP from the ER to lysosomes and auto-
phagosomes [20]. Both full-length and fragmented APP exist at sev-
eral unusual locations viz. nucleus [21], the ciliary root of retinal
photoreceptor cells [22], mitochondria [23], and cytoplasm [24]. APP
intracellular domain (APP fragment) can either enter the nucleus
alone or in combination with Fe65 and APP binding protein [21].
This localization mode suggests a novel target that could aid in AD
therapy. Other widely used strategies for AD therapy are the preven-
tion of A generation, improvement in proper APP processing
through inhibition of -, - or -secretase enzymes [25, 26].
1.2. Amyloid Beta (A)
Amyloid beta peptides are formed by the action of various se-
cretase enzymes which lead to the formation of amyloid plaques
[27]. Numerous studies demonstrated lower A42 density in cere-
bro spinal fluid (CSF) of AD patients [28, 29]. This notion is not
clearly understood but it is believed that A42 confiscation to
plaques is the main reason behind the reduced clearance of A into
CSF [30]. On the other hand, Creuztfeldt-Jakob disease patients
also have decreased levels of A clearance but they did not have
any amyloid plaque deposition [31]. Hence, the decreased clearance
of A is believed to be due to the different mechanisms that take
place in various diseases. A recent study provided a notion that

1875-5453/17 $58.00+.00 © 2017 Bentham Science Publishers

Exploration of Various Proteins for the Treatment of Alzheimer’s Disease
NON-AMYLOIDOGENIC PATHWAY
a-Secretase g-Secretase
Amyloid Precursor Protein (APP)
b-Secretase g-Secretase
AMYLOIDOGENIC PATHWAY
Fig. (1). Amyloidogenic and non-amyloidogenic pathway depicting APP cleavage by secretase enzymes.
decreased A42 clearance in AD patients is most probably due to
the accumulation of A42 monomers into oligomers that results
into epitope camouflaging accompanied by conformational altera-
tions and making them inaccessible to antibodies [32]. Furthermore,
this assumption is supported by the oligomerization of A42 in the
brain parenchyma of AD patients.
The possible A targeting approaches are listed below:
Reducing A Production: It can be achieved either by the activating
-secretase or inhibiting - and -secretase enzymes.
tio y
Arresting A Oligomerization or Fibrillization: A peptides have
bu nl
the ability to self-aggregate that leads to the formation of oli-
n
gomers, protofibrils, fibrils and finally A plaques [33, 34]. A
tri O
vast array of molecules has been recognized that could either
arrest A aggregation and fibrillogenesis or hinder A toxicity.
Congo red (A fibril binding dye) has been reported to inhibit
is e
fibril generation along with their beneficial effect on neurotox-
icity [35, 36]. Other compounds such as sulfonated anions, sul-
s
fonated dyes (benzofuran-type compounds) and amphiphilic
rD U
surfactants (di-C6-PC and di-C7-PC) have also been reported
for A inhibiting potential [37-39]. One study reported clear-
ance of amyloid plaque by active immunization with A (AN
Fo al
1792) in AD patients [40]. Tramiprosate (glycosaminoglycan)
arrest the A oligomerization and fibril formation by interact-
ing with A monomers while bapineuzumab (humanized
ot on
monoclonal antibody against A1-5) interact with both soluble
and fibrillar forms of A that decreases amyloid load in trans-
genic mice [41-43]. Another compound ELND005 or scyllo-
N rs
inositol also inhibits A oligomerization by reducing soluble
A, hence reverses the cognitive decline in transgenic mice
Pe
[44]. Colostrinin (a proline-rich peptide) has been reported for
its anti-aggregation property that results in the dissolution of
pre-formed fibrils [45]. Recently, several new peptides with
anti-aggregation potential have been synthesized [46]. An ac-
tin-binding protein, gelsolin plays an essential role in the as-
sembly and disassembly of actin filaments and is extracellu-
larly found in CSF and plasma and intracellularly in mito-
chondria and cytosol [47]. It has the ability to hamper A fi-
brillization and helps in the dissolution of preformed A fi-
brils, which increases its clearance [48].
Increasing A Clearance: Several proteases, such as angiotensin-
converting enzyme (ACE), insulin degrading enzyme (IDE),
cathepsin B, metalloproteinase 9, neprilysin and plasmin, play
a major role in the digestion of A plaques and their decline
may lead to retention of A in AD patients [49-51]. ACE has
been reported to notably arrest A aggregation, retention, and
cytotoxicity [52]. IDE is expressed in almost all tissues but
greatly in testis, brain, liver and muscle and has A digesting
capability [53-55]. Therefore, strategies that could increase the
expression and activity of IDE could also be exploited as a po-
tential approach for AD therapy. Cathepsin B (a cysteine pro-
tease), appreciably decreases A deposition through degrada-
tion of A1-42 at C-terminal and believed to reduce its level in
AD brain [56, 57]. Somatostatin, a peptide hormone, modu-
lates the A removal via neprilysin activation [58]. Therefore,
Current Drug Metabolism, 2017, Vol. 18, No. 9 809
P3 Peptides
Amyloid Beta (Ab) Ab Oligomers Ab Fibrils Ab Plaques
monomers
employing somatostatin or its analogs to target neprilysin
could be a good therapeutic approach in AD therapy. RAGE-
mediated active transport is the target of interest for the scien-
tists as it transports A across the blood-brain barrier and aid
in their deposition. Hence the use of RAGE inhibitors is con-
sidered as another therapeutic option in AD therapy. One of
RAGE inhibitors (PF-04494700) has successfully completed
phase 2 trials. Different monoclonal antibodies have the ability
to bind A and aid in their clearance via microglial phagocyto-
sis [59]. Solanezumab (LY2062430), a humanized monoclonal
antibody against A16-24, binds with soluble A [60] whereas
gantenerumab (R1450, a monoclonal antibody against A1-
11) and crenezumab (humanized monoclonal antibody against
A40/A42) have been reported to decrease cerebral A
through microglial phagocytosis [61, 62].
1.3. Tau Protein
Tau is a microtubule-associated protein, commonly expressed
in neurons, where it primarily takes part in microtubule stabilization
(comprising nucleation, growth, and bundling), thereby regulates
functional organization of the neuronal cells [63]. C-terminal end of
tau protein contains microtubule-binding domain that is involved in
the polymerization and stabilization of microtubules [64]. Whereas
N-terminal is composed of highly acidic amino acids followed by
proline-rich area. This domain is involved in the interaction be-
tween cytoskeleton and plasma membrane [65]. Phosphorylated tau
interacts with microtubules with reduced affinity resulting in the
instability of microtubules. This reduction in microtubule stability
leads them into filamentous and non-filamentous aggregates that
convert into neurotoxic NFTs and neuritic plaques at later stage
[66]. The focal point of AD pathogenesis is tau hyperphosphoryla-
tion that causes microtubule instability [67].
Tau targeting strategies are depicted in Fig. (2) and are also
listed below:
Preventing Tau Phosphorylation: Kinase blocking is one of the
convincing strategy to prevent tau phosphorylation. Various
tau kinases capable of phosphorylating tau are cyclin-
dependent protein kinase 5 (cdk5), glycogen synthase kinase
3 (GSK-3), stress-activated protein kinase (SAPK), micro-
tubule affinity-regulating kinase (MARK), eukaryotic transla-
tion initiation factor 2 alpha kinase 2 (EIF2AK2), dual-
specificity tyrosine (Y)-phosphorylation regulated kinase 1A
(DYRK1A), A-kinase anchor protein 13 (AKAP-13) and
cAMP-dependent protein kinase (PKA) have been listed in lit-
erature [68-70]. Most studies reported lithium as the main
blocker of GSK-3 however, several other compounds such as
sodium valproate, flavopiridol, aloisines, aminothiazole AR-
A014418, pyrazolopyridines and pyrazolopyrazines have also
been reported for GSK-3 blocking activity. Likewise, cdk5
inhibitors like indirubins, purine olomoncine, aloisines and
flavopiridol are also considered for this purpose [69, 71].
Moreover, several important signaling pathways are actively
regulated by the kinases, therefore one should consider the
possible side effects caused by the use of kinase blockers [72,
810 Current Drug Metabolism, 2017, Vol. 18, No. 9 Islam et al.

Tau Targeting Strategies

Prevention of tau
phosphorylation
1. Blockage of various
kinases (cdk5, GSK-3b,
SAPK, MARK, etc.)
2. Activation of phosphatases
by drugs such as metformin
and sodium selenite
Prevention of microtubule
destabilization by the use of
1. Paclitaxel
2. Epothilone D
3. Neuropeptides such as
NAP and D-SAL
Block tau oligomerization or Increasing tau digestion Increasing tau
aggregation by the use of clearance
1. Hsp90 inhibitors 1. Immunological-based
1. Tau-binding drugs such as such as curcumin approach such as use
lansoprazole and astemizole of monoclonal
antibodies against
2. Methylene blue phosphorylated tau
3. Natural phenolic
compounds
(hydroxytyrosol, oleuropein,
oleurpein aglycone, etc.)

Fig. (2). A representative diagram highlighting strategies for tau-targeting.

Table 1. Management of AD through various protein targeting and their molecular participants.

Targeted protein Strategies Participants References

tio y
Amyloid precursor protein (APP) Prevention in amyloid beta (A) generation. Inhibition of - or -secretase enzymes. [25, 26]

bu nl
Improvement in proper APP processing. Inhibition of -, - or -secretase enzymes. [25, 26]

n
tri O
Amyloid beta (A) Reduction in A production. Activation of -secretase or inhibition of [30, 32]
- and -secretase enzymes.

Arresting A oligomerization. Tramiprosate, ELND005 and colostrinin. [41, 44-45]

is e
Arresting A fibrillization. Congo red, gelsolin, bapineuzumab and [35, 37-39,
s
amphiphilic surfactants. 42, 43, 48]
rD U

Increase in A clearance via digestion of A. Angiotensin-converting enzyme, insulin [49-51]

degrading enzyme, cathepsin B,
Fo al

metalloproteinase 9, neprilysin and plasmin.

ot on

Increase in A clearance via neprilysin activation. Somatostatin. [58]

Increase in A clearance via active transport. RAGE inhibitors. [59]

N rs

Increase in A clearance via microglial phagocytosis. Solanezumab, gantenerumab and crenezumab. [61, 62]

Tau protein Prevention in tau phosphorylation by Lithium, sodium valproate, flavopiridol, [69, 71]
Pe

kinase inhibitors. indirubins, purine olomoncine, aloisines etc.

Prevention in tau phosphorylation by phosphatase Metformin, sodium selenite and memantine. [74, 75]
activators.

Reduction in microtubule destabilization. Paclitaxel, epothilone D, and neuropeptides. [76-78]

Prevention in tau oligomerization/aggregation. Lansoprazole, astemizole, methylene blue [79-84]

and natural phenolic compounds.

Acceleration in tau digestion. Hsp90 inhibitors. [86, 87]

Increase in tau clearance. Monoclonal antibodies against [89, 90]

phosphorylated tau.

73]. Another strategy to dephosphorylate tau is the activation
of protein phosphatases. The key enzyme involved in tau-
based dephosphorylation is protein phosphatase 2A (PP2A),
thus its activators are believed to have therapeutical potential
in AD treatment. Drugs, such as metformin and memantine
have been reported for PP2A activating properties [74, 75]. On
the other hand, sodium selenite (Ve-015), a PP2A activator, is
under clinical investigation.
Reduction in Microtubule Destabilization: Paclitaxel (a strong anti-
cancer drug), is reported for microtubule stabilization poten-
tials, such as improvement in microtubule density, motor func-
tion, and axonal transport. Another compound, epothilone D
has also been noted for microtubule stabilization effects be-
sides blood-brain barrier clearance potential [76]. Neuropep-
tides, such as NAP and D-SAL, have also been documented
for boosting effect on microtubule stabilization [77, 78].
Blocking Tau Oligomerization/Aggregation: One of the important
tau-based AD treatment approaches is to find out the com-
pounds that could block tau interaction and NFT deposition.
Tau-binding drugs, such as lansoprazole and astemizole, are
Exploration of Various Proteins for the Treatment of Alzheimer’s Disease
indirectly helpful in reducing tau-tau interactions thereby ar-
resting tau oligomerization/aggregation [79]. Methylene blue
has been documented for various effects that include preven-
tion of tau interactions, amyloid aggregation, acetylcholine es-
terase inhibition, reduction in oxidative stress, improvement in
electron transport and mitochondrial damage aversion [80-83].
Daccache et al. [84] reported naturally occurring phenolic
compounds (hydroxytyrosol, oleuropein and its derivative
oleuropein aglycone) with tau arresting properties [84].
Accelerating Tau Digestion: Tau breakage is also considered as a
promising treatment option against AD pathogenesis. Chaper-
ones, like Hsp90, involved in the prevention of tau breakage
besides its role in proper folding of denatured proteins [85].
Curcumin (Hsp90 inhibitors) has also been reported for tau
breaking potential [86, 87]. However, the only concern related
with chaperone blocking is the probable intrusion in their main
activity may cause adverse effects.
Increasing Tau Clearance: Immunological based approach for
clearance of tau and its related fibrils receives interest lately
[88]. Scientific studies reported beneficial effects in tau trans-
genic mice when they were passively immunized with mono-
tio y
clonal antibodies against phosphorylated tau [89, 90]. This
suggests a potential of immune based approach for the AD
bu nl
treatment. We have also summarized various protein targeting
n
approaches in the Table (1).
tri O
CONCLUSION
In view of the current article and above-mentioned literature,
is e
we emphasize the exploitation of various proteins and their novel
inhibitors for the clinical treatment of AD. The pathogenesis of AD
s
is highly complex and several factors and signaling mechanisms
rD U
actively participate in it. FDA-approved treatments for AD fail to
stop or slow-down disease progression and are related to adverse
side effects that decrease patient interest to therapy. Hence, its
Fo al
treatment still needs new refinements and approaches for novel
targets in search to achieve complete endeavor.
ot on
CONSENT FOR PUBLICATION
Not applicable.
N rs
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
Pe
wise.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the research facility pro-
vided by the Aligarh Muslim University, Aligarh, India and King
Fahd Medical Research Center (KFMRC), King Abdulaziz Univer-
sity, Jeddah, Saudi Arabia. Thanks are also due to Mohammad S
Gazdar (Librarian, KFMRC) for providing assistance with the
literature.
REFERENCES
[1] Ballard, C.; Gauthier, S.; Corbett, A.; Brayne, C.; Aarsland, D.;
Jones, E. Alzheimer's disease. Lancet, 2011, 377, 1019-1031.
[2] Mullane, K.; Williams, M. Alzheimer's therapeutics: Continued
clinical failures question the validity of the amyloid hypothesis-but
what lies beyond? Biochem. Pharmacol., 2013, 85, 289-305.
[3] Silva, T.; Reis, J.; Teixeira, J.; Borges, F. Alzheimer's disease,
enzyme targets and drug discovery struggles: from natural products
to drug prototypes. Ageing Res. Rev., 2014, 15, 116-145.
[4] Alzheimer’s Association. 2015 Alzheimer's disease facts and fig-
ures. Alzheimers Dement., 2015, 11, 332-384.
[5] Noble, W.; Hanger, D.P.; Miller, C.C.J.; Lovestone, S. The impor-
tance of tau phosphorylation for neurodegenerative diseases. Front.
Neurol., 2013, 4, 83.
[6] De-Paula, V.J.; Radanovic, M.; Diniz, B.S.; Forlenza, O.V. Alz-
heimer’s disease. Subcell. Biochem., 2012, 65, 329-352.
Current Drug Metabolism, 2017, Vol. 18, No. 9 811
[7] Lacor, P.N.; Buniel, M.C.; Furlow, P.W.; Clemente, A.S.; Velasco,
P.T.; Wood, M.; Viola, K.L.; Klein, W.L. Abeta oligomer-induced
aberrations in synapse composition, shape, and density provide a
molecular basis for loss of connectivity in Alzheimer’s disease. J.
Neurosci., 2007, 27, 796-807.
[8] Wenk, G.L. Neuropathologic changes in Alzheimer’s disease. J.
Clin. Psychiat., 2003, 64, S7-S10.
[9] Goedert, M.; Spillantini, M.G. A century of Alzheimer's disease.
Science, 2006, 314, 777-781.
[10] Bezprozvanny, I.; Mattson, M.P. Neuronal calcium mishandling
and the pathogenesis of Alzheimer's disease. Trends Neurosci.,
2008, 31, 454-463.
[11] Praticò, D. Evidence of oxidative stress in Alzheimer's disease
brain and antioxidant therapy: Lights and shadows. Ann. N. Y.
Acad. Sci., 2008, 1147, 70-78.
[12] Trepanier, C.H.; Milgram, N.W. Neuroinflammation in Alzheimer's
disease: are NSAIDs and selective COX-2 inhibitors the next line
of therapy? J. Alzheimers Dis., 2010, 21, 1089-1099.
[13] Craig, L.A.; Hong, N.S.; McDonald, R.J. Revisiting the cholinergic
hypothesis in the development of Alzheimer's disease. Neurosci.
Biobehav. Rev., 2011, 35, 1397-1409.
[14] Bonda, D.J.; Lee, H.G.; Blair, J.A.; Zhu, X.; Perry, G.; Smith, M.A.
Role of metal dyshomeostasis in Alzheimer's disease. Metallomics,
2011, 3, 267-270.
[15] Selkoe, D.J. The cell biology of beta-amyloid precursor protein and
presenilin in Alzheimer's disease. Trends Cell Biol., 1998, 8, 447-
453.
[16] Walter, J.; Haass, C. Posttranslational modifications of amyloid
precursor protein: Ecto domain phosphorylation and sulfation.
Methods Mol. Med., 2000, 32, 149-168.
[17] Muresan, V.; Muresan, Z. Is abnormal axonal transport a cause, a
contributing factor or a consequence of the neuronal pathology in
Alzheimer's disease? Future Neurol., 2009, 4, 761-773.
[18] Kojro, E.; Gimpl, G.; Lammich, S.; Marz, W.; Fahrenholz, F. Low
cholesterol stimulates the nonamyloidogenic pathway by its effect
on the alpha-secretase ADAM 10. Proc. Natl. Acad. Sci. USA,
2001, 98, 5815-5820.
[19] Selkoe, D.J.; Schenk, D. Alzheimer's disease: molecular under-
standing predicts amyloid-based therapeutics. Annu. Rev. Pharma-
col. Toxicol., 2003, 43, 545-584.
[20] Xiao, Q.; Yan, P.; Ma, X.; Liu, H.; Perez, R.; Zhu, A.; Gonzales,
E.; Tripoli, D. L.; Czerniewski, L.; Ballabio, A.; Cirrito, J. R.; Di-
wan, A.; Lee, J. M. Neuronal-targeted TFEB accelerates lysosomal
degradation of APP, reducing A
generation and amyloid plaque
pathogenesis. J. Neurosci., 2015, 35, 12137-12151.
[21] Cao, X.; Südhof, T.C. A transcriptionally [correction of transcrip-
tively] active complex of APP with Fe65 and histone acetyltrans-
ferase Tip60. Science, 2001, 293, 115-120.
[22] Yang, J.; Li, T. The ciliary rootlet interacts with kinesin light
chains and may provide a scaffold for kinesin-1vesicular cargos.
Exp. Cell Res., 2005, 309, 379-389.
[23] Anandatheerthavarada, H.K.; Biswas, G.; Robin, M.A.; Avadhani,
N. G. Mitochondrial targeting and a novel transmembrane arrest of
Alzheimer's amyloid precursor protein impairs mitochondrial func-
tion in neuronal cells. J. Cell Biol., 2003, 161, 41-54.
[24] Takahashi, R.H.; Milner, T.A.; Li, F.; Nam, E.E.; Edgar, M.A.;
Yamaguchi, H.; Beal, M.F.; Xu, H.; Greengard, P.; Gouras, G.K.
Intraneuronal Alzheimer a beta 42 accumulates in multivesicular
bodies and is associated with synaptic pathology. Am. J. Pathol.,
2002, 161, 1869-1879.
[25] Schenk, D.; Basi, G.S.; Pangalos, M.N. Treatment strategies target-
ing amyloid
-protein. Cold Spring Harb. Perspect. Med., 2012, 2,
a00638.
[26] Saido, T.; Leissring, M.A. Proteolytic degradation of amyloid
-
protein. Cold Spring Harb. Perspect. Med., 2012, 2, a006379.
[27] Kang, J.; Lemaire, H.G.; Unterbeck.; Salbaum, J.M.; Masters, C.L.;
Grzeschik, K.H.; Multhaup, G.; Beyreuther, K.; Müller-Hill, B.
The precursor of Alzheimer's disease amyloid A4 protein resembles
a cell-surface receptor. Nature, 1987, 325, 733-736.
[28] Blennow, K.; De Leon, M.J.; Zetterberg, H. Alzheimer’s disease.
Lancet, 2006, 368, 387-403.
[29] Shaw, L.M.; Vanderstichele, H.; Knapik-Czajka, M.; Figurski, M.;
Coart, E.; Blennow, K.; Soares, H.; Simon, A.J.; Lewczuk, P.;
Dean, R.A.; Siemers, E.; Potter, W.; Lee, V.M.; Trojanowski, J.Q.
Alzheimer's disease neuroimaging initiative. qualification of the
812 Current Drug Metabolism, 2017, Vol. 18, No. 9
analytical and clinical performance of CSF biomarker analyses in
ADNI. Acta. Neuropathol., 2011, 121, 597-609.
[30] Fagan, A.M.; Mintun, M.A.; Mach, R.H.; Lee, S.Y.; Dence, C.S.;
Shah, A.R.; LaRossa, G.N.; Spinner, M.L.; Klunk, W.E.; Mathis,
C.A.; DeKosky, S.T.; Morris, J.C.; Holtzman, D.M. Inverse rela-
tion between in vivo amyloid imaging load and cerebrospinal fluid
Abeta42 in humans. Ann. Neurol., 2006, 59, 512-519.
[31] Wiltfang, J.; Esselmann, H.; Smirnov, A.; Bibl, M.; Cepek, L.;
Steinacker, P.; Mollenhauer, B.; Buerger, K.; Hampel, H.; Paul, S.;
Neumann, M.; Maler, M.; Zerr, I.; Kornhuber, J.; Kretzschmar, H.
A.; Poser, S.; Otto, M. Beta-amyloid peptides in cerebrospinal fluid
of patients with Creutzfeldt-Jakob disease. Ann. Neurol., 2003, 54,
263-267.
[32] Wang-Dietrich, L.; Funke, S. A.; Kuhbach, K.; Wang, K.;
Besmehn, A.; Willbold, S.; Cinar, Y.; Bannach, O.; Birkmann, E.;
Willbold, D. The amyloid-beta oligomer count in cerebrospinal
fluid is a biomarker for Alzheimer’s disease. J. Alzheimers Dis.,
2013, 34, 985-994.
[33] Xu, Y.; Shen, J.; Luo, X.; Zhu, W.; Chen, K.; Ma, J.; Jiang, H.
Conformational transition of amyloid beta-peptide. Proc. Natl.
Acad. Sci. USA, 2005, 102, 5403-5407.
[34] Ahmed, M.; Davis, J.; Aucoin, D.; Sato, T.; Ahuja, S.; Aimoto, S.;
Elliott, J.I.; Van Nostrand, W. E.; Smith, S.O. Structural conversion
of neurotoxic amyloid-
1-42 oligomers to fibrils. Nat. Struct. Mol.
tio y
Biol., 2010, 17, 561-567.
[35] Lorenzo, A.; Yankner, B.A. Beta-amyloid neurotoxicity requires
bu nl
fibril formation and is inhibited by Congo red. Proc. Natl. Acad.
n
Sci. USA, 1994, 91, 12243-12247.
tri O
[36] De Felice, F.G.; Ferreira, S.T. Beta-amyloid production, aggrega-
tion, and clearance as targets for therapy in Alzheimer's disease.
Cell Mol. Neurobiol., 2002, 22, 545-563.
[37] Kisilevsky, R.; Lemieux, L.J.; Fraser, P.E.; Kong, X.; Hultin, P.G.;
is e
Szarek, W.A. Arresting amyloidosis in vivo using small-molecule
anionic sulphonates or sulphates: implications for Alzheimer's dis-
s
ease. Nat. Med., 1995, 1, 143-148.
rD U
[38] Allsop, D.; Howlett, D.; Christie, G.; Karran, E. Fibrillogenesis of
beta-amyloid. Biochem. Soc. Trans., 1998, 26, 459-463.
[39] Wang, S.S.; Chen, Y.T.; Chou, S.W. Inhibition of amyloid fibril
formation of beta-amyloid peptides via the amphiphilic surfactants.
Fo al
Biochim. Biophys. Acta., 2005, 1741, 307-313.
[40] Serrano-Pozo, A.; William, C. M.; Ferrer, I.; Uro-Coste, E.;
ot on
Delisle, M.B.; Maurage, C.A.; Hock, C.; Nitsch, R.M.; Masliah, E.;
Growdon, J.H.; Frosch, M.P.; Hyman, B.T. Beneficial effect of
human anti-amyloid-beta active immunization on neurite morphol-
ogy and tau pathology. Brain, 2010, 133, 1312-1327.
N rs
[41] Wright, T.M. Tramiprosate. Drugs Today (Barc), 2006, 42, 291-
298.
Pe
[42] Teich, A.F.; Arancio, O. Is the amyloid hypothesis of Alzheimer’s
disease therapeutically relevant? Biochem. J., 2012, 446, 165-177.
[43] Bard, F.; Cannon, C.; Barbour, R.; Burke, R.L.; Games, D,; Gra-
jeda, H.; Guido, T.; Hu, K.; Huang, J.; Johnson-Wood, K.; Khan,
K.; Kholodenko, D.; Lee, M.; Lieberburg, I.; Motter, R.; Nguyen,
M.; Soriano, F.; Vasquez, N.; Weiss, K.; Welch, B.; Seubert, P.;
Schenk, D.; Yednock, T. Peripherally administered antibodies
against amyloid beta-peptide enter the central nervous system and
reduce pathology in a mouse model of Alzheimer disease. Nat.
Med., 2000, 6, 916-919.
[44] DaSilva, K.A.; Brown, M.E.; Cousins, J.E.; Rappaport, R.V.; Au-
bert, I.; Westaway, D.; McLaurin, J. scyllo-inositol (ELND005)
ameliorates amyloid pathology in an aggressive mouse model of
Alzheimer’s disease. Alzheimer’s Demen., 2009, 5, P425.
[45] Janusz, M.; Woszczyna, M.; Lisowski, M.; Kubis, A.; Macala, J.;
Gotszalk, T.; Lisowski, J. Ovine colostrum nanopeptide affects
amyloid beta aggregation. FEBS Lett., 2009, 583, 190-196.
[46] Luo, Y.; Vali, S.; Sun, S.; Chen, X.; Liang, X.; Drozhzhina, T.;
opugaeva, E.; Bezprozvanny, I. Abeta42-Binding peptoids as amy-
loid aggregation inhibitors and detection ligands. ACS Chem. Neu-
rosci., 2013, 4, 952-962.
[47] Kwiatkowski, D.J.; Mehl, R.; Yin, H.L. Genomic organization and
biosynthesis of secreted and cytoplasmic forms of gelsolin. J. Cell.
Biol., 1988, 106, 375-384.
[48] Chauhan, V.; Ji, L.; Chauhan, A. Anti-amyloidogenic, anti-oxidant
and antiapoptotic role of gelsolin in Alzheimer’s disease. Biogeron-
tology, 2008, 9, 381-389.
Islam et al.
[49] Nalivaeva, N.N.; Beckett, C.; Belyaev, N.D.; Turner, A.J. Are
amyloid-degrading enzymes viable therapeutic targets in Alz-
heimer’s disease? J. Neurochem., 2012, 120 (Suppl. 1), 167-185.
[50] Barage, S.H.; Sonawane, K.D. Amyloid cascade hypothesis:
Pathogenesis and therapeutic strategies in Alzheimer's disease.
Neuropeptides, 2015, 52, 1-18.
[51] Yasojima, K.; McGeer, E.G.; McGeer, P.L. Relationship between
beta amyloid peptide generating molecules and neprilysin in Alz-
heimer disease and normal brain. Brain Res., 2001, 919, 115-121.
[52] Hu, J.; Igarashi, A.; Kamata, M.; Nakagawa, H. Angiotensin-
converting enzyme degrades Alzheimer amyloid beta-peptide (A
beta); retards A beta aggregation, deposition, fibril formation; and
inhibits cytotoxicity. J. Biol. Chem., 2001, 276, 47863-47868.
[53] Kuo, W.L.; Montag, A.G.; Rosner, M.R. Insulin-degrading enzyme
is differentially expressed and developmentally regulated in various
rat tissues. Endocrinology, 1993, 132, 604-611.
[54] Vekrellis, K.; Ye, Z.; Qiu, W. Q.; Walsh, D.; Hartley, D.;
Chesneau, V. Neurons regulate extracellular levels of amyloid beta-
protein via proteolysis by insulin-degrading enzyme. J. Neurosci.,
2000, 20, 1657-1665.
[55] Farris, W.; Mansourian, S.; Chang, Y.; Lindsley, L.; Eckman, E.
A.; Frosch, M.P.; Eckman, C.B.; Tanzi, R.E.; Selkoe, D.J.;
Guenette, S. Insulin-degrading enzyme regulates the levels of insu-
lin, amyloid beta-protein, and the beta-amyloid precursor protein
intracellular domain in vivo. Proc. Natl. Acad. Sci. USA, 2003, 100,
4162-4167.
[56] Mueller-Steiner, S.; Zhou, Y.; Arai, H.; Roberson, E.D.; Sun, B.;
Chen, J.; Wang, X.; Yu, G.; Esposito, L.; Mucke, L.; Gan, L.
Antiamyloidogenic and neuroprotective functions of cathepsin B:
implications for Alzheimer's disease. Neuron, 2006, 51, 703-714.
[57] Sun, B.; Zhou, Y.; Halabisky, B.; Lo, I.; Cho, S. H.; Mueller-
Steiner, S.; Devidze, N.; Wang, X.; Grubb, A.; Gan, L. Cystatin C-
cathepsin B axis regulates amyloid beta levels and associated neu-
ronal deficits in an animal model of Alzheimer's disease. Neuron,
2008, 60, 247-257.
[58] Saito, T.; Iwata, N.; Tsubuki, S.; Takaki, Y.; Takano, J.; Huang, S.
M.; Suemoto, T.; Higuchi, M.; Saido, T. C. Somatostatin regulates
brain amyloid beta peptide Abeta42 through modulation of prote-
olytic degradation. Nat. Med., 2005, 11, 434-439.
[59] Wisniewski, T.; Konietzko, U. Amyloid-beta immunisation for
Alzheimer's disease. Lancet Neurol., 2008, 7, 805-811.
[60] Teich, A. F.; Arancio, O. Is the amyloid hypothesis of Alzheimer’s
disease therapeutically relevant? Biochem. J., 2012, 446, 165-177.
[61] Ostrowitzki, S., Deptula, D.; Thurfjell, L.; Barkhof, F.; Bohrmann,
B.; Brooks, D.J.; Klunk, W.E.; Ashford, E.; Yoo, K.; Xu, Z.X.;
Loetscher, H.; Santarelli, L. Mechanism of amyloid removal in pa-
tients with Alzheimer disease treated with gantenerumab. Arch.
Neurol., 2012, 69, 198-207.
[62] Adolfsson, O.; Pihlgren, M.; Toni, N.; Varisco, Y.; Buccarello, A.
L.; Antoniello, K.; Lohmann, S.; Piorkowska, K.; Gafner, V.; At-
wal, J. K.; Maloney, J.; Chen, M.; Gogineni, A.; Weimer, R.M.;
Mortensen, D.L.; Friesenhahn, M.; Ho, C.; Paul, R.; Pfeifer, A.;
Muhs, A.; Watts, R.J. An effector-reduced anti-
-amyloid (A
) an-
tibody with unique A
binding properties promotes neuroprotection
and glial engulfment of A
. J. Neurosci., 2012, 32, 9677-9689.
[63] Buée, L.; Bussière, T.; Buée-Scherrer, V.; Delacourte, A.; Hof, P.
R. Tau protein isoforms, phosphorylation and role in neurodegen-
erative disorders. Brain Res. Brain Res. Rev., 2000, 33, 95-130.
[64] Goedert, M.; Spillantini, M.G.; Potier, M.C.; Ulrich, J.; Crowther,
R. A. Cloning and sequencing of the cDNA encoding an isoform of
microtubule-associated protein tau containing four tandem repeats:
Differential expression of tau protein mRNAs in human brain.
EMBO J., 1989, 8, 393-399.
[65] Brandt, R.; Leger, J.; Lee, G. Interaction of tau with the neural
plasma membrane mediated by tau's amino-terminal projection
domain. J. Cell. Biol., 1995, 131, 1327-1340.
[66] Spillantini, M. G. Tauopathies: a single therapy for all? Neurobiol.
Aging, 2012, 3, S34.
[67] Sergeant, N.; Bretteville, A.; Hamdane, M.; Caillet-Boudin, M.L.;
Grognet, P.; Bombois, S.; Blum, D.; Delacourte, A.; Pasquier, F.;
Vanmechelen, E.; Schraen-Maschke, S.; Buée, L. Biochemistry of
Tau in Alzheimer's disease and related neurological disorders. Exp.
Rev. Proteom., 2008, 5, 207-224.
[68] Ferrer, I.; Gomez-Isla, T.; Puig, B.; Freixes, M.; Ribe, E.; Dalfo,
E.; Avila, J. Current advances on different kinases involved in tau
 Exploration of Various Proteins for the Treatment of Alzheimer’s Disease
phosphorylation, and implications in Alzheimer's disease and
tauopathies. Curr. Alzheimer Res., 2005, 2, 3-18.
[69] Mazanetz, M.P.; Fischer, P.M. Untangling tau hyperphosphoryla-
tion in drug design for neurodegenerative diseases. Nat. Rev. Drug
Discov., 2007, 6, 464-479.
[70] Himmelstein, D.S.; Ward, S.M.; Lancia, J.K.; Patterson, K.R.;
Binder, L.I. Tau as a therapeutic target in neurodegenerative dis-
ease. Pharmacol. Ther., 2012, 136, 8-22.
[71] Churcher, I. Tau therapeutic strategies for the treatment of Alz-
heimer's disease. Curr. Top. Med. Chem., 2006, 6, 579-595.
[72] Wang, J.Z.; Grundke-Iqbal, I.; Iqbal, K. Kinases and phosphatases
and tau sites involved in Alzheimer neurofibrillary degeneration.
Eur. J. Neurosci., 2007, 25, 59-68.
[73] Gong, C.X.; Iqbal, K. Hyperphosphorylation of microtubule-
associated protein tau: A promising therapeutic target for Alz-
heimer disease. Curr. Med. Chem., 2008, 15, 2321-2328.
[74] Chohan, M.O.; Khatoon, S.; Iqbal, I.G.; Iqbal, K. Involvement of
I2PP2A in the abnormal hyperphosphorylation of tau and its rever-
sal by memantine. FEBS Lett., 2006, 589, 3973-3979.
[75] Kickstein, E.; Krauss, S.; Thornhill, P.; Rutschow, D.; Zeller, R.;
Sharkey, J.; Williamson, R.; Fuchs, M.; Köhler, A.; Glossmann, H.;
Schneider, R.; Sutherland, C.; Schweiger, S. Biguanide metformin
acts on tau phosphorylation via mTOR/protein phosphatase 2A
(PP2A) signaling. Proc. Natl. Acad. Sci. USA, 2010, 107, 21830-
tio y
21835.
[76] Andrieux, A.; Salin, P.; Schweitzer, A.; Begou, M.; Pachoud, B.;
bu nl
Brun, P.; Gory-Fauré, S.; Kujala, P.; Suaud-Chagny, M. F.; Höfle,
n
G.; Job, D. Microtubule stabilizer ameliorates synaptic function
tri O
and behavior in a mouse model for schizophrenia. Biol. Psychiat.,
2006, 60, 1224-1230.
[77] Gozes, I.; Divinski, I.; Piltzer, I. NAP and D-SAL: neuroprotection
against the beta amyloid peptide (1-42). BMC Neurosci., 2008, 9
is e
(Suppl. 3), S3.
[78] Gozes, I. NAP (davunetide) provides functional and structural
s
neuroprotection. Curr. Pharm. Des., 2011, 17, 1040-1044.
rD U
[79] Rojo, L.E.; Alzate-Morales, J.; Saavedra, I.N.; Davies, P.; Mac-
cioni, R.B. Selective interaction of lansoprazole and astemizole
with tau polymers: potential new clinical use in diagnosis of Alz-
heimer’s disease. J. Alzheimers Dis., 2010, 19, 573-589.
Fo al
[80] Congdon, E.E.; Wu, J.W.; Myeku, N.; Figueroa, Y.H.; Herman,
M.; Marinec, P.S.; Gestwicki, J.E.; Dickey, C.A.; Yu, W.H.; Duff,
ot on
K.E. Methylthioninium chloride (methylene blue) induces auto-
N rs
Pe
View publication stats
Current Drug Metabolism, 2017, Vol. 18, No. 9 813
phagy and attenuates tauopathy in vitro and in vivo. Autophagy,
2012, 8, 609-622.
[81] Necula, M.; Breydo, L.; Milton, S.; Kayed, R.; van der Veer, W.
E.; Tone, P.; Glabe, C.G. Methylene blue inhibits amyloid Abeta
oligomerization by promoting fibrillization. Biochemistry, 2007,
46, 8850-8860.
[82] Pfaffendorf, M.; Bruning, T.A.; Batnik, H.D.; van Zwieten, P.A.
The interaction between methylene blue and the cholinergic sys-
tem. Br. J. Pharmacol., 1997, 122, 95-98.
[83] Atamna, H.; Nguyen, A.; Schultz, C.; Boyle, K.; Newberry, J.;
Kato, H.; Ames, B.N. Methylene blue delays cellular senescence
and enhances key mitochondrial biochemical pathways. FASEB J.,
2008, 22, 703-712.
[84] Daccache, A.; Lion, C.; Sibille, N.; Gerard, M.; Slomianny, C.;
Lippens, G.; Cotelle, P. Oleuropein and derivatives from olives as
Tau aggregation inhibitors. Neurochem. Int., 2011, 58, 700-707.
[85] Dickey, C.A.; Kamal, A.; Lundgren, K.; Klosak, N.; Bailey, R.M.;
Dunmore, J.; Ash, P.; Shoraka, S.; Zlatkovic, J.; Eckman, C.B.;
Patterson, C.; Dickson, D. W.; Nahman, N. S. Jr.; Hutton, M.; Bur-
rows, F.; Petrucelli, L. The high-affinity HSP90-CHIP complex
recognizes and selectively degrades phosphorylated tau client pro-
teins. J. Clin. Invest., 2007, 117, 648-658.
[86] Giommarelli, C.; Zuco, V.; Favini, E.; Pisano, C.; Dal Piaz, F.; De
Tommasi, N.; Zunino, F. The enhancement of antiproliferative and
proapoptotic activity of HDAC inhibitors by curcumin is mediated
by Hsp90 inhibition. Cell Mol. Life Sci., 2010, 67, 995-1004.
[87] Ma, Q.L.; Zuo, X.; Yang, F.; Ubeda, O.J.; Gant, D.J.; Alaverdyan,
M.; Teng, E.; Hu, S.; Chen, P.P.; Maiti, P.; Teter, B.; Cole, G. M.;
Frautschy, S. A. Curcumin suppresses soluble tau dimers and cor-
rects molecular chaperone, synaptic, and behavioral deficits in aged
human tau transgenic mice. J. Biol. Chem., 2013, 288, 4056-4065.
[88] Rosenmann, H. Immunotherapy for targeting tau pathology in
Alzheimer’s disease and tauopathies. Curr. Alzheimer Res., 2013,
10, 217-228.
[89] Boutajangout, A.; Ingadottir, J.; Davies, P.; Sigurdsson, E.M. Pas-
sive immunization targeting pathological phospho-tau protein in a
mouse model reduces functional decline and clears tau aggregates
from the brain. J. Neurochem., 2011, 118, 658-667.
[90] Chai, X.; Wu, S.; Murray, T.K.; Kinley, R.; Cella, C.V.; Sims, H.;
Buckner, N.; Hanmer, J.; Davies, P.; O'Neill, M.J.; Hutton, M.L.;
Citron, M. Passive immunization with anti-Tau antibodies in two
transgenic models: Reduction of Tau pathology and delay of dis-
ease progression. J. Biol. Chem., 2011, 286, 34457-34467.