Brain Research Reviews 23 Ž1997.

134–143

Short Review

Advanced glycation endproducts in ageing and Alzheimer’s disease

a,)
¨
Gerald Munch , Johannes Thome b, Paul Foley b, Reinhard Schinzel a , Peter Riederer b

a
Physiological Chemistry I, Theodor-BoÕeri-Institut (Biozentrum), Am Hubland, 97074 Wurzburg,
¨ Germany
b
¨
Clinical Neurochemistry, Department of Psychiatry, Fuchsleinstraße ¨
15, 97080 Wurzburg, Germany
Accepted 29 July 1996

Abstract

Accumulation of advanced glycation endproducts ŽAGE. in the brain is a feature of ageing and degeneration, especially in Alzheimer’s
disease ŽAD.. Increased AGE levels explain many of the neuropathological and biochemical features of AD such as extensive protein
crosslinking Žß-amyloid and MAP-t ., oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback
loop, where normal age-related changes develop into a pathophysiological cascade. Combined intervention using antioxidants, metal
chelators, anti-inflammatory drugs and AGE-inhibitors may be a promising neuroprotective strategy.

Keywords: Advanced glycation end product; Neurodegeneration; Oxidative stress; Alzheimer’s disease; Plaque; Tangle; Neurotoxicity

Contents

1. Advanced glycation endproducts: chemistry . ...................................................... 135

2. Advanced glycation endproducts in ageing and degenerative diseases of the cardiovascular system . ......................... 136

3. Accumulation of advanced glycation endproducts in brain in ageing and in Alzheimer’s disease ........................... 136

4. Toxic effects of advanced glycation endproducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

4.1. Radical induced damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
4.2. Induction of oxidative stress through binding to an advanced glycation endproduct receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
4.3. Inhibition of differentiation factor mediated neurite outgrowth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
4.4. Inhibition of protein turnover by advanced glycation endproducts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138

5. Factors for increased advanced glycation endproduct formation in Alzheimer’s disease . ............................... 138

6. Advanced glycation endproduct inhibitors: definition and proposed mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ 139
6.1. Carnosine: a physiological advanced glycation endproduct inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ 139
6.2. Synthetic advanced glycation endproduct inhibitors: a new therapeutic opportunity for the treatment of Alzheimer’s disease? . ........ 139

7. Advanced glycation endproducts and their role in Alzheimer’s disease — a critical evaluation . ........................... 140

8. Conclusion ........................................................................ 141

Acknowledgements . ..................................................................... 141

References .......................................................................... 141

)
Corresponding author. Fax: q49 Ž931. 888-4150; E-mail: muench@biozentrum.uni-wuerzburg.de

0165-0173r97r$32.00 Copyright q 1997 Elsevier Science B.V. All rights reserved.

PII S 0 1 6 5 - 0 1 7 3 Ž 9 6 . 0 0 0 1 6 - 1
 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch 135

1. Advanced glycation endproducts: chemistry Table 1

Reactivities of different sugars Žwith ß-alanine as amino component. in
the Maillard reaction Žfrom w47x.
The amino groups of proteins, particularly the N-termi-
nal amino groups and side chains of lysine and arginine Sugar formation of radical formation
chromophores Žintensity of ESR
react non-enzymatically with monosaccharides, including Žbrowning. spectra.
glucose, fructose, hexose-phosphates, trioses and triose-
Glucose ŽC-6. 1 qq
phosphates. This posttranslational modification, termed Fruktose ŽC-6. 0.74 q
‘non-enzymatic glycosylation’, ‘glycation’ or ‘Maillard re- Xylose ŽC-5. 8.74 qq
action’, leads via reversible Schiff-base adducts to protein Mehylglyoxal ŽC-3. 654 not determined
bound Amadori products. Through subsequent oxidations Glyceraldehyde ŽC-3. 1967 qqq
and dehydrations, including free radical intermediates, a Glycolaldehyde ŽC-2. 2109 qqqq
broad range of heterogeneous fluorescent and yellow-brown
products with nitrogen- and oxygen-containing heterocy-
cles is formed, the so-called advanced glycation endprod-
ucts ŽAGEs. w4,5x. These latter reactions are accelerated by can be inhibited by metal chelators, emphasising the signif-
transition metals, such as copper and iron, which oxidise icance of transition metals for AGE-formation w76x. Among
the protein-bound Amadori-products. In this ‘glycoxida- the physiologically relevant sugars, glucose is the least
tion’ reaction not only protein-bound AGEs, but also solu- reactive, presumably the reason for its selection by evolu-
ble, highly reactive dicarbonyl products and oxygen free tion as the main biological energy carrier; the rank order of
radicals are formed. By an alternative route, transition reactivity for the other monosaccharides increases from
metals can oxidise the monosaccharides directly in solu- hexoses to trioses by several orders of magnitude ŽTable 1.
tion to form dicarbonyl products, which subsequently w47x. AGE formation is irreversible and causes protease-re-
crosslink proteins; this process is called ‘autooxidative sistant cross-linking of peptides and proteins, leading to
glycosylation’ w75x. The oxidation steps in both pathways protein deposition and amyloidosis ŽFig. 1..

Fig. 1. Chemistry of advanced glycation endproducts.

136 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch
2. Advanced glycation endproducts in ageing and de-
generative diseases of the cardiovascular system
In the early 80’s, Monnier and Cerami, the pioneers of
the ‘non-enzymatic glycosylation theory of ageing’ pro-
posed that the AGE-mediated crosslinking of long-lived
proteins contributes to the age-related decline in the func-
tion of cells and tissues in normal ageing w4,42,43,64x.
Recent progress in the understanding of this process has
confirmed that AGEs play a significant role in the evolu-
tion of vascular complications in normal ageing, especially
in diabetes and renal failure. AGEs have been detected in a
variety of vascular wall, lipoprotein and lipid constituents,
where they lead to macroangiopathy, microangiopathy and
amyloidosis. In particular, diseases such as atherosclerosis,
cataract and diabetic nephropathy, retinopathy and neu-
ropathy are suggested to be either caused or promoted by
AGEs ŽTable 2. w4,52x. The detrimental effects of AGEs in
pathological processes were originally attributed to their
physicochemical properties including protein crosslinking
but more recent studies increasingly emphasise the role of
AGEs in cellular processes and signalling events, espe-
cially in the oxidative stress response. In diabetes, acceler-
ated AGE formation is caused primarily by a higher level
of plasma glucose and, intracellularly, by activation of the
polyol pathway. In hemodialysis patients, similar cardio-
vascular complications as in diabetic patients were ob-
served, which led to the speculation that AGEs may be
also involved. These patients show an increased amount of
AGEs with a molecular weight of about 2 kDa in their
plasma, suggesting this may be caused by the inability of
the dialysis cartridges to remove these low molecular
weight AGE-modified peptides w16,53,71x. However, the
factors responsible for the increased cerebral AGE levels
in Alzheimer’s disease ŽAD. are not yet fully understood.
3. Accumulation of advanced glycation endproducts in
brain in ageing and in Alzheimer’s disease
AGEs accumulate in pyramidal neurons in aged animals
Žhorse, calf, pig, and rat. and humans, but their intra-
cellular distribution pattern is quite different between ani-
mal and man. In the human pyramidal neuron, AGEs
exhibit a granular, perikaryonal distribution, whereas in
Table 2
Human degenerative diseases with a proposed involvement of AGEs
Failure of maintenance Major pathologies
in cells or tissues
Neurones Dementias
Retina, lens Blindness
Insulin metabolism, signalling Complications of diabetes
Blood vessels Cardiovascular diseases
Glomeruli Renal failure
animal brains, AGEs show a nuclear staining pattern w34x.
Pyramidal neurons selectively accumulate AGE-containing
vesicles in an age-dependent manner presumably in endo-
somes or lysosomes w30,35x. Interestingly, this type of
neuron degenerates early in AD w35x. However, the AGE-
antibodies used in the study by Li et al. were raised against
an uncharacterised polylysine-glucose mixture and the re-
sults should be interpreted rather cautiously.
The histological hallmarks of AD include widespread
neuronal cell death and the formation of amyloid plaques
and neurofibrillary tangles. AGE modification and result-
ing crosslinking of protein deposits has been shown to
occur in both plaques and tangles which is not unexpected
since various long-lived and precipitated proteins become
modified by AGEs.
In detail, increased extracellular AGE formation has
been demonstrated in amyloid plaques in different cortical
areas w63,68x. In another immunohistochemical study vas-
cular walls in amyloid angiopathy were not labelled by a
monoclonal antibody, while primitive plaques, coronas of
classic plaques and some glial cells in Alzheimer’s cortex
were positive for AGEs w29x. These findings suggest that
AGE formation may occur in the early stages in plaque
formation in Alzheimer’s disease, but AGE-epitopes disap-
pear when the plaque ages or undergoes processing by
astrocytes and microglia. There are only a few studies
published so far showing that AGE formation not only
occurs subsequent to protein deposition, but actively accel-
erates their formation from soluble protein or peptide
precursors. We and others could show that nucleation-de-
pendent polymerization of ß-amyloid peptide, the major
component of plaques in patients with Alzheimer’s dis-
ease, is significantly accelerated by crosslinking through
AGEs in vitro w45,68x. This suggests, that AGE may
indeed represent a driving force in the acceleration of
ß-amyloid deposition and plaque formation. Numerous
studies have shown that susceptibility to AD is correlated
with the dose of the e4 allele of apolipoprotein E ŽApo E.
w12,31x. Harrington and Colaco suggested that consequent
substitution of cysteines by arginines creates more glyca-
tion sites and hence facilitates the AGE-mediated cross-
linking of Apo E to the insoluble deposits and hence
accelerates plaque growth w20x.
Neurofibrillary tangles ŽNFT. and neuropil threads are
further histological characteristics of Alzheimer’s disease
w78x. The rate of progression of Alzheimer’s disease-re-
lated neurofibrillary changes is unknown, but initial
changes occur 50 years before the disease is diagnosed
w2,3x. The major component of these tangles is the micro-
tubuli associated protein t ŽMAP-t ., which has been
shown to be subject to intracellular hyperglycation and
AGE formation w64x. Further, MAP-t is glycated at its
tubulin binding site, and MAP-t glycated in vitro is capa-
ble of inducing oxidative stress w33,77x. The protein con-
stituents of NFT are resistant to proteolytic removal, possi-
bly as a result of extensive cross-links w10x. Although it is
 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch
reasonable to accept the idea of AGE-modification of
extracellular tangles, it is not clear to what extent glycation
is involved in the first steps of intracellular tangle forma-
tion, especially when one considers the established cross-
linking and aggregation mechanism such as formation of
specific disulfide bridges and hyperphosphorylation w36,60x
or formation of core fragments of MAP-t w50x.
In summary, among the many factors proposed to be
involved in the etiology or progression of Alzheimer’s
disease, AGEs are a relatively new and interesting ap-
proach to unravel the mysteries of the etiopathogenesis of
this multifactorial disease. However, one has to be careful
not to overestimate their role in the disease process as long
as only circumstantial evidence is presented that they are
active promotors of the progression, not only simply a
secondary epiphenomenon in Alzheimer’s disease w56x.
4. Toxic effects of advanced glycation endproducts
AGEs have been shown to be more than a harmless
post-translational protein modification; various pathophysi-
ological effects have been found at the cellular and molec-
ular level. Among the proposed mechanisms of AGE-in-
duced damage are the following four.
4.1. Radical induced damage
Associated with the oxidation of sugars and Amadori
products is the formation of oxygen free radicals. Protein
glycation increases the rate of free radical production at
physiological pH nearly 50-fold compared with non-
Fig. 2. Activation of microgliarmacrophages by AGE-modified protein Že.g., ß-amyloid. deposits and resulting cytotoxicity.
137
glycated protein w46x. This process commences with the
production of superoxide radicals by transition metal-cata-
lysed autoxidation of the sugars and protein bound Amadori
products, followed by dismutation of superoxide to hydro-
gen peroxide and the generation of lethal hydroxyl radicals
by the Fenton reaction. This leads to a site-specific attack
on the protein with consequent protein damage and lipid
peroxidation w64x.
AGE can also produce oxygen free radicals through an
indirect, immune system mediated process. Interaction of
AGE-modified proteins with microglia in an acute phase
reaction can lead to a ‘respiratory burst’. This radical
challenge has been shown to cause ‘bystander-lysis’ of
neighbouring neurons ŽFig. 2. w41x. AGEs have been shown
to induce inflammatory processes in regions other than the
brain such as activation of peripheral macrophages w18x
and chemotaxis of mononuclear phagocytes w57x. AGEs
also induce the release of cytokines such as interleukins 1
and 6, as well as of TNF-a w70x. Interestingly, IL-6
immunoreactivity has previously been demonstrated in
plaques in Alzheimer’s disease, and elevated IL-6 concen-
trations have been measured in brains of AD patients w26x.
This concurs with the finding that an autodestructive pro-
cess, involving overactive astroglia and microglia, occurs
at the characteristic lesions in Alzheimer disease w39,40,73x.
4.2. Induction of oxidatiÕe stress through binding to an
adÕanced glycation endproduct receptor
Binding of AGEs to specific receptors can generate
oxidative stress, as measured chemically by the production
138 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch
of thiobarbituric acid-reactive substances. It might be pos-
sible, that this occurs through an oxidative signalling path-
way or through internalisation of AGEs by one of the
many characterized AGE-receptors. Beside one recently
described receptor for AGEs, RAGE w57–59,74x and other
receptors and receptor complexes with binding specificity
for AGEs w56,69,72x, it is known that the macrophage
scavenger receptor ŽMSR. mediates the endocytic uptake
and degradation of AGE proteins w1x. In the brain, this
receptor is expressed on microglia, but not on astrocytes,
neurons, or vessel-associated structures. In Alzheimer dis-
ease, there is strong expression of the scavenger receptor
in association with senile plaques w11x.
Oxidative stress in AD it is not only evidenced by
chemical markers w17x but also by the activation of the
antioxidative defence system, such as the activation of the
transcription factor NFk B and the upregulation of heme
oxygenase. These AGE-mediated effects can be blocked
by addition of antioxidants, such as probucol, or of anti-
bodies to the AGE-receptor w74x. In AD tissue, accumu-
lated paired helical filament-t in neurons is also subject to
non-enzymatic glycation and AGE formation, and these
neurons also exhibit evidence of oxidative stress, including
the production of malondialdehyde and the heme oxyge-
nase 1 antigen. In cell culture experiments, PHF-t isolated
from post mortem tissue and recombinant AGE-t each
generate oxygen free radicals, thereby not only activating
transcription via NFk B, but also increasing APP levels
and inducing the release of the characteristic 4-kDa ß-
amyloid-peptides w58,77x.
4.3. Inhibition of differentiation factor mediated neurite
outgrowth
One putative receptor for advanced glycation end prod-
ucts ŽRAGE., a member of the immunoglobulin superfam-
ily, mediates interactions of AGE-modified proteins with
endothelium and other cell types. AGE binding to this type
of receptors not only induces an oxidative stress response
but may also antagonise the binding of other specific
physiological ligands. RAGE has physiologically relevant
ligands distinct from AGEs, including amphoterin, which
mediates neurite outgrowth in the developing CNS. A
non-specific interference with such growth or differentia-
tion factors may also be a pathophysiological effect of
AGEs w23x.
4.4. Inhibition of protein turnoÕer by adÕanced glycation
endproducts
It has been speculated that a general proteolytic imbal-
ance in the AD brain contributes to the accumulation of
amyloid plaques and neurofibrillary tangles w62x. AGE-
modification not only contributes to protein crosslinking, it
also decreases the susceptibility to proteolysis and degra-
dation, which would be expected to shift the metabolic
balance in the direction of deposition rather than degrada-
tion. Proteins modified by sugars more reactive than glu-
cose, such as fructose, are more resistant to proteolysis,
suggesting that proteolysis is a complex process dependent
on the various protein-bound moieties generated at differ-
ent stages of the Maillard reaction w65x. Metabolic transit
experiments have shown, that the AGE moieties them-
selves can only be degraded by the bacteria found in the
digestive tract, but not directly by the host w15x. We have
shown that the activity of certain proteases Žcathepsins.
and the total cellular protein turnover are attenuated in
cells exposed to synthetic AGEs w61x.
5. Factors for increased advanced glycation endproduct
formation in Alzheimer’s disease
AGEs play an important role in the evolution of vascu-
lar complications in normal ageing as discussed in Section
2. AGEs in diabetes are generally associated with a higher
level of plasma glucose and in renal failurerhemodialysis
by the inability of the dialysis cartridges to remove AGE-
modified peptides w4,16,71x. However, many additional
factors including the involvement of C-3 and C-2 sugars
and fragmentation products, even oxidised ascorbate w48x,
as well as transition metals and oxidative stress contribute
to AGE formation in different tissues. Although thor-
oughly investigated for about nearly 20 years, the chem-
istry and biochemistry of glycoxidation are very complex
and many critical issues, such as tissue and protein specific
glycemic thresholds w49x, still have to be resolved. In
analogy to diabetes, many of the factors mentioned above
may explain the elevated level of AGEs and AGE
crosslinked proteins in the brain tissue of AD patients. In
detail, the following three specific changes in AD may
contribute to this process:
Ži. an intracellular increase in particular AGE reactive
sugars as the consequence of a disturbed glucose
metabolism w24,25x;
Žii. an increase in unchelated transition metals such as
copper and iron, acceleration of the oxidation of glycated
proteins and subsequent increase in highly reactive glycox-
idation products w9,75x,
Žiii. depletion of the antiglycation substance pool, for
example the histidine dipeptides including carnosine and
anserine w21,22x.
Interestingly, the increased level of cerebral AGEs in
AD patients is not reflected by an increased AGE level in
plasma w67x. This is not an unexpected finding as an
increased AGE plasma level would lead to cardiovascular
complications and the dementia would be classified as a
vascular type dementia. In summary, cerebral AGE accu-
mulation in AD is probably a highly selective, brain
specific event.
 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch
6. Advanced glycation endproduct inhibitors: definition
and proposed mechanism
An AGE-inhibitor is usually defined as a substance,
which inhibits the covalent crosslinking of proteins and
peptides by sugars or sugar derived oxidation products. It
contains a nucleophilic amino group which competes with
lysines side chains of proteins for reactive carbonyl or
dicarbonyls groups formed on proteins and in solution.
Since the crucial step of AGE crosslinking depends on the
presence of transition metals for the formation of glycoxi-
dation products and radicals, metal chelators and radical
scavengers, especially superoxide dismutase mimetics,
could also be regarded as AGE-inhibitors in a broader
sense of the definition. Several natural and synthetic com-
pounds ŽFig. 3. have been shown to be inhibitors of
AGE-formation in vitro and in vivo w6,19x.
6.1. Carnosine: a physiological adÕanced glycation end-
product inhibitor
The dipeptide carnosine Žß-alanyl-L-histidine. is widely
distributed in mammalian tissues, including muscle and
brain with concentrations of up to 20mM w28,51x. It is
synthesised by tissue carnosine synthetase from its compo-
nent amino acids, and degraded by carnosinase, predomi-
nantly in plasma. Various biological functions of carnosine
have been demonstrated, including its role as a antioxidant,
metal-chelator, SOD mimetic and radical scavenger w55x.
One of the most prominent effects of carnosine is its
anti-ageing properties including as life span extension and
the prevention of the appearance of the usual signs of
late-passage senescence Žinability to line up in parallel
arrays in a confluent monolayer. in fibroblasts cells w38x.
Interestingly, carnosine concentrations in skeletal muscle
correlates with the life-span of the corresponding animal
ŽFig. 4. w7,37,55x. In addition, histidine dipeptide levels
Žcarnosine, anserine, etc.. decrease in skeletal and cardiac
muscles in ageing rats w28x. Although the data in both
studies seem reliable, in general, claims that certain drugs
or physiological substances which decline with age, corre-
late with life span or can even be used for its extension,
should be analyzed very critically.
Fig. 3. Chemical structures of the AGE-inhibitors aminoguanidine, carno-
sine and tenilsetam.
139
Fig. 4. Correlation of skeletal muscle carnosine concentration with lifes-
pan in different animals.
Carnosine inhibits glycation of acetyl-Lys-His-amide
Žthe preferred glycation site on proteins. and protects
model proteins Že.g., a-crystalline, superoxide dismutase
and catalase. against glycation and AGE cross-linking
w21,22x. Mammals thus possess strategies using physio-
logical AGE-inhibitors such as carnosine which minimise
glycation and AGE-formation. Dysfunction of the physio-
logical AGE-defence and -clearance mechanisms could
underlie a variety of degenerative diseases, including
Alzheimer’s disease. On the other hand, supplementing
naturally occurring anti-glycation molecules by synthetic
AGE-inhibitors, especially in tissues with low concentra-
tions of natural compounds could be an effective therapeu-
tic strategy for Alzheimer’s disease.
6.2. Synthetic adÕanced glycation endproduct inhibitors: a
new therapeutic opportunity for the treatment of
Alzheimer’s disease?
Aminoguanidine was the ‘pioneering’ AGE-inhibitor,
which was first tested in in vitro crosslinking experiments,
then shown in various animal models to attenuate the
AGE-mediated vascular complications of diabetes w6,19x.
Tenilsetam , Ž q . -3- Ž 2-thienyl . -2-piperazinone, a
cognition-enhancing and a purportedly anti-dementia drug
was also shown to be an effective AGE inhibitor, although
its mechanism is yet not fully understood. Tenilsetam
reacts with sugars and glycated proteins and acts as an
inhibitor of AGE-induced amino acid and protein cross-
linking in vitro w44x. Tenilsetam, aminoguanidine and
carnosine significantly inhibit nucleation-dependent poly-
merisation of ß-amyloid peptide with similar efficacy w45x.
The positive effects of AGE-inhibitors with respect to the
reduction of ß-amyloid toxicity may be attributable to
formation of ‘masked’, less toxic AGE peptide aggregates.
AGE-inhibitors could also shift the metabolic AGE bal-
ance in the direction of degradation and clearance rather
than accumulation. AGE-inhibitors could also modify the
structure of AGEs in a way which inhibits their binding to
140 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch
and recognition by AGE receptors. These mechanisms
might subsequently lead to a diminished inflammatory
response and decreased oxidative stress ŽFig. 5.. However,
these are quite speculative hypotheses and need substantial
investigations at the molecular and cellular level before
incorporating them into the etiopathogenesis of AD w66x.
However, some pharmacological support for these hy-
potheses comes from the first clinical trial with an AGE-
inhibitor, tenilsetam, in AD patients. This drug signifi-
cantly improved many clinical and psychometric scores
including shortening of P300 latencies in the acoustic
evoked potential, global clinical impression, Sandoz clini-
cal assessment geriatric scale, Folstein minimental state
scale and shopping list w13,27x. Interestingly, the improve-
ment had not reached a plateau when the study was ended
after three months. Although a direct cholinergic mecha-
nism was initially assumed for tenilsetam, there was no
evidence for muscarinic acetylcholine receptor binding or
acetylcholine re-uptake inhibition. No evidence for an
alternative neuroprotective mechanism such as free radical
scavenging was found. However, the slow appearance of
clinical improvement suggests that the efficacy in
Alzheimer’s patients may be indeed due to interference
with post-translational modification of proteins. Tenilse-
tam, a non-charged molecule, crosses the blood brain
barrier, but the effects of the charged AGE-inhibitors
Fig. 5. Suggested role of AGEs in the pathogenesis of Alzheimer’s disease and points of possible therapeutic intervention with AGE-inhibitors.
carnosine and aminoguanidine might be limited to the
cardiovascular system, if they are not actively transported
across the blood brain barrier.
Despite some circumstantial evidence that the beneficial
effect of tenilsetam in AD patients supports the involve-
ment of AGEs in pathological processes in the late stages
of AD, a direct attenuation of cytotoxic AGE effects by
AGE-inhibitors has to be shown at least before proposing
this as a valid approach for the treatment of AD patients.
7. Advanced glycation endproducts and their role in
Alzheimer’s disease — a critical evaluation
Alzheimer’s disease, the most common dementing dis-
order of late life, is a major cause of disability and death in
the elderly. Neurobiological, genetic, and molecular stud-
ies have defined the vulnerable neural systems, including
abnormalities in cytoskeletal proteins in neurons, the biol-
ogy of the beta-amyloid precursor protein and its prote-
olytic cleavage product, beta-amyloid w12,14,54x. The mul-
tifactorial puzzle of the disease includes most likely a
combination of age-related degenerative changes with ad-
ditional genetic predispositions and environmental factors
determining the vulnerability of the individual. Although
there might be various different critical triggering events in
 ¨ et al.r Brain Research ReÕiews 23 (1997) 134–143
G. Munch
the early stages of the disease, they seem to converge on a
few characteristic final pathways in the late stages of the
disease. It seems reasonable to believe, that not the initial
events, but the later steps most likely offer the most
promising pharmalogical approaches for slowing down the
progression of the disease.
However, before a specific treatment by AGE-inhibitors
can be proposed for AD, it has to be proven beyond doubt
that AGEs are more than just a harmless post-transational
protein modification, but an irreversible promoter of cross-
linking and maybe even a cytotoxic substance. It has been
shown, that AGEs accelerate the formation and inhibit the
removal of AGE-modified protein deposits w5,45,68x. If
these proteins, e.g., the ß-amyloid peptide, are toxic them-
selves w32x, this might be enough to suggest a ‘supporting
role’ of AGEs in the pathogenesis of AD. However, it is
necessary to investigate if AGEs themselves exert a direct
toxicity to cells. Studies about the indirect neurotoxicity of
AGEs by activation of microglia and subsequent radical
and cytokine release seem to be quite sound, but it is not
clear, if this event in AD occurs before the neurons have
been already irreversibly damaged.
At this point of time, it seems quite speculative and
premature to propose a specific treatment of AD with
AGE-inhibitors as a rational approach to the treatment of
the disease, as long as a direct attenuation of the direct or
indirect cytotoxic effects of AGEs in cell culture or in an
animal model by AGE-inhibitors have not been shown.
However, one has to keep in mind, that there is no
promising alternative treatment for AD avaliable, since the
beneficial effects of cholinergic substitution therapy has
definitely fallen short of expectations w8x.
8. Conclusion
Many of the degenerative changes described in AD,
such as increased oxidative stress and formation of AGEs
resemble processes seen in other diseases including late
complications in diabetes and long term hemodialysis. The
‘glycation theory of ageing’ as the underlying common
principle of degeneration unites most of the neuropatholog-
ical and biochemical findings in AD to a general picture.
AGE formation explains accelerated protein crosslinking
with ß-amyloid and MAP-t, increased oxidative stress, and
direct as well as indirect immune system mediated induc-
tion of neuronal cell death w20,64x. In particular, oxidative
stress and AGEs amplify each others’ effects and produce
a positive feedback loop of degeneration. If this vicious
circle cannot be physiologically managed, normal age-re-
lated alterations become a pathological cascade resulting in
irreversible damage. Pharmacological intervention using
antioxidants, metal chelators and AGE-inhibitors may be a
promising combined approach for minimising AGE forma-
tion in ageing and degeneration in general and, especially,
the resulting pathological effects in Alzheimer’s disease.
141
Acknowledgements
We thank A. Hipkiss, J. Michaelis, R. Holliday, U.
Schindler, A.M. Cunningham, M. Atkinson and J. Shine
for valuable and critical discussions and the ‘Claussen-
Stiftung’ and the ‘Hirnliga e.V.’ for funding.
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