Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : July 20, 2014
Accepted : November 6, 2014
Published online : December 31, 2014

Review article

Role of advanced glycation end products in Alzheimer's disease
Barić Nikola
Private General Practice Office, Labin, Croatia

Abstract

Population ageing, particularly in developed countries, is accompanied with an increased incidence of chronic degenerative
diseases, including those affecting the central nervous system, such as dementia and Alzheimer's disease (AD). AD is a serious
disease that follows a progressive course, but can be difficult to recognize initially due to a variable onset time. AD gradually
becomes more evident and destructive, leading to decreased immune resistance and the development of comorbidities, andeventually to total incapacity and death. In addition, because the cost associated with the medical treatment and care of AD
patients is becoming an enormous financial burden of health care systems, there is considerable interest in determining the causes
underlying the onset and progression of AD, which have not yet been clearly defined. Genetic predisposition has been identified
as a crucial factor; however, recent evidence suggests that reactive oxygen species and the activity of advanced glycation end
products (AGEs) also substantially contribute to AD. Although a few studies have suggested that AGEs have minimal importancein AD, an increasing number of scientists believe that AGEs play a central role in the development of this disease due to thesignificant accumulation of these compounds in senile plaques and neurofibrillary tangles, which are the key indicators of AD.
Evidence suggests that AGEs activate receptors of AGEs (RAGE) on neurons, astrocytes and glia, leading to oxidative stress anda cascade of biochemical activities that severely damage neuronal cells. In the present review, recent findings on AGEs in AD, as
well as advances in therapeutic approaches related to this disease,

KEY WORDS: population ageing, chronic degenerative diseases, Alzheimer's disease, oxidative stress, glycative stress,
advanced glycation end products (AGEs)

Introduction

Accompanied with the dramatic rise in the proportionof elderly people ( ≥ 65 years of age) in economicallydeveloped countries, the prevalence and incidence of chronic
degenerative diseases, primarily cardiovascular, osteomuscularand neurodegenerative disorders, has markedly increased.
Among neurodegenerative disorders, the increased incidence
of dementias, particularly Alzheimer's disease (AD), is ofparticular concern.

AD is characterized by a progressive deterioration inmental, cognitive, and body function that leads to a complete
inability to respond to the environment or control movement,
eventually leading to death 1- 6 ) . It starts by mild cognitive
disturbances even a few years before the exact diagnosis.
It occurs with the decline in the ability to remember recent
events and to learn new informations and skills. AD isgenerally expressed in two main forms: early onset familial
AD (autosomal dominant familial AD, which comprises <1~5% of all cases, and late-onset AD (sporadic AD), which
comprises 95% of all cases. There are no data about theother types of AD ( Table 1 ). Studies indicate that earlyAddress correspondence to:Barić Nikola MD, PhD
Private General Practice Office with Doppler Ultrasound Diagnostics,
Presika 153, 52220 Labin, Istra, Croatia
e-mail: nikola.baric@pu.htnet.hr_ 68 _

onset AD is associated with mutations in the amyloid
precursor ( APP ) gene (chr.21q21), presenilin 1 (PSEN-1;
chr.14) and 2 (PSEN-2; chr.1) genes, and beta-secreatase 1(BACE1; chr.11q23.3) gene. Presenilin is a component of γ
secretase and mutations of its gene are a strong risk factor
for early-onset AD. Gamma (γ) and ß secretases cleave APP
and generate Aß; PSEN1 chr.14; PSEN2 chr.1; BACE1
chr11, ß-secretase. Although the late-onset form of AD
is attributable to several causes, it is also associated withseveral identified gene mutations, including the A POE ε 4allele (chr.19), TREM 2 gene (chr. 6p21.1), and ADAM 10
gene (chr. 15q21.3) ( Table 2 ) 5, 6).
What is the cause of AD? Although the exact cause isunknown, evidence to date suggests that there are several
contributing factors. The aim of this review is to present
recent findings about the involvement of beta amyloid (Aß)
protein in the onset and course of AD. In addition, a numberof studies have investigated the contribution of advanced
glycation end products (AGEs) in the etiology of AD, as
knowledge necessary for understanding the pathology
and pathophysiology of disease, and possibly lead to thedevelopment of effective therapies.

Glycative Stress Research 2014; 1 (4): 68-83(c) Society for Glycation Stress ResearchGlycative Stress Research

Pathology of AD

Two types of characteristic fibrous lesions are associatedwith AD: extracellular senile plaques (SPs) and intracellular
neurofibrillary tangles (NFTs). The critical component of
SP are Aß peptides, while tau protein is the main componentof NFT. Aß peptide is derived from the cleavage of amyloid
precursor protein (APP) and is subsequently glycated with
reducing sugars, including glucose, lactose, and galactose, in
AGE compounds, which are toxic compounds for the body
( Fig. 1 ).
Both Aß peptides and Aß-AGEs are ligands for the
receptor for AGEs (RAGE), which is a transmembraneprotein located in the brain on neurons, astrocytes, microglia,
and vascular endothelial cell membranes. Activation of
RAGE induces a strong biochemical cascade mediated by
the glycogen synthase kinase-3 (GSK-3) pathway, leading toatherogenic gene activation. Aß-AGEs are formed during
the nonenzymatic glycosylation or glycation of Aß peptides
with reducing sugars, such as glucose, lactose, and galactose.
The characteristic SP and NFT lesions of AD are primarily
located in the cortical gray matter, hippocampus andamygdaloid nuclei. The quantity of Aß and Aß-AGEs in SPs
is directly associated with the intensity of AD symptoms( Figs. 1- 4 ) 7 - 14 ) . AGE compounds damage neuronal cellsin two ways: through the crosslinking essential protein
molecules and by interaction with RAGE and its associatedligands.

Elevated Aß peptide concentrations generated via
positive biofeedback mechanisms induce RAGE expression.
Two important enzymes, ß and γ secretase, induce theintramembranous cleavage of APP and Aß peptide formation.
Importantly, the activities of these two enzymes are elevated in
AD patients. RAGE expression is also greatly elevated in AD
brains, leading to increased Aß peptide transport through theblood brain barrier (BBB) 7).
AGEs are formed through the Maillard reaction in a seriesof slow spontaneous nonenzymatic biochemical reactions.
During the Maillard reaction, which is also known as glycationor the browning reaction ( Fig. 2 ), the carbonyl group (C=O)
of a reducing sugar binds with the amino group (NH 2 ) of aprotein molecule side chain 7-14).
AD manifests in two forms: autosomal dominant familial
AD (early-onset familial AD), which comprises only 1%~5%cases), and a more common sporadic form ( late-onset AD[LOAD]), which represents 95% cases ( Table 1 ). Early-onset
AD is relatively rare and is strongly associated with mutationsin the genes encoding presenilin, which is a component of theγ secretase enzyme that cleave APP and generates Aß peptide.
In contrast, the sporadic form of AD represents the majority ofcases and is typically observed in patients over 65 years of age
This form of AD is associated with mutations in the ADAM
10 gene (MGH-MIND Genetics and Aging Research Unit,
Massachusetts) TREM 2 gene (chromosome 6p21.1), whichleads to a 3 to 5-fold greater risk for AD. Two mutations havebeen identified in ADAM 10 that lower its α-secretase activity,

Table 1. Forms of Alzheimer's disease (AD) according to the onset and cause.
Disease form

Characteristics/features

Autosomal-dominant familial AD(Early-onset genetic form of familial AD)

・Accounts for ≤ 5% of AD cases
・onset before 65 years of age
・primarily due to mutations in APP,

Sporadic AD (Late-onset AD)・most cases of AD
・autosomal dominant heredity not indicated・dominance of apolipoprotein E (APOE)
・associated with mutations in ADAM10, TREM2

PSEN1 (presenilin 1; chr.14) or PSEN2 (presenilin 2; chr.1) genes

A. Autosomal-dominant familial Alzheimer’s disease( Early-onset genetic form of familial AD)
Accounts for ≤ 5% of AD cases – onset before 65 years;
primarily due to mutations in
APP, PSEN1 (presenilin 1) or PSEN2 (presenilin 2);

B. Sporadic form of AD(Late-onset AD [LOAD]) most cases of AD;
autosomal dominant heredity not indicated;dominance of apolipoprotein E (APOE)ADAM 10 gene (published 2013. - MGH-MIND Genetics and Aging Research Unit, Massachusetts);
TREM 2 gene (mutations associated with a 3 to 5-fold greater risk for AD);mutations in 13 GWAS genes (genome-wide association studies) – intensive multicentric investigations about the possible genetic inclination to LOAD; studies are
conducted by Alzheimer’s Disease Genetics Consortium granted by the National Institute on Aging (USA);_ 69 _

AGEs in Alzheimer's diseaseleading to reduced cleavage of the Aß region of APP and
decreased production of protective protein (sAPPα) (Tanzi andSuh, 2013). TREM2 is a microglial receptor-triggering receptor
expressed on myeloid cells 2 that plays an important role incontrolling the quantity of Aß peptide in the brain.
A number of hypotheses to explain the underlying
biochemical mechanisms of AD have been proposed
and include the cholinergic hypothesis, tau hypothesis,
mitochondrial AD cascade hypothesis ( Fig. 7 ), and amyloid
hypothesis. In addition, the following factors may be involvedin the development of AD: Herpes simplex virus type 1, age,sex, Down syndrome (trisomy 21), trauma, stress, diet richwith AGE compounds, aluminium in diet, and heart disease,particularly atrial fibrillation. However, the exact cause(s) of
AD have yet to be conclusively demonstrated .

Formation of SPs and NFTs

Two hallmark pathologies of AD, SPs and NFTs, arefound in the brain tissues of patients, particularly in the
cerebral cortex, hippocampus, and amygdaloid nuclei. BothSPs, which are primarily located near synapses, and NFTs aremainly composed of Aß peptide, tau protein, and Aß-AGE
glycation-derived compounds. Experimental evidence suggeststhat the formation of these lesions is strongly dependent on
the nonenzymatic glycosylation of APP-derived Aß peptides.
Aß peptides are typically 39~42 amino acids in length, andaccumulate in the brain, leading to the onset and progressionof AD ( Figs. 1- 4 ). The proteolysis of APP is induced byß and γ secretases results in the fragmentation of APP andformation of Aß peptide the transmembrane domain of APP. In
AD, the proteolytic activity of ß and γ secretases is elevated,

Table 2. Presentation of elementary symptoms in the four stages of AD.
AD Stage

Characteristics/features

1. Predementia

・Decline in directed attention and abstract thinking
・Reduced ability to comprehend reason-consequence
・Apathy and depression are frequent comorbidities
・Agitation and irritability

2. Early stage of defined disease・Clear decrease in ability to learn new content
・Drop in spectrum of used words and fluidity of speaking
・Marked decrease in memory, particularly new data

3. Middle stage・Decline in reading and writing ability
・Reduced ability to recollect words necessary for conversation
・Drop in motor activity
・Decreased short-term memory
・Frequent inability to recognize friends and family
・Frequent episodes of agitation, aggressiveness, and tearfulness
・Urinary incontinence may occur

4. Advanced stage

・Complete dependency on caregivers
・Speech indiscernible or lacking
・Frequently aggressive and/or extremely apathetic
・Strong decline in muscular strength (inability to stand or walk)・Strong decline in immunity and increased incidence of acute infections(pneumonia or other infective diseases), which are often fatal

1. Stage: Predementia

Decline in directed attention
Decline in abstract thinking
Reduced ability to comprehend composed links – type reason-consequence isgreatly reduced
Apathy and depression are frequent comorbidities
Agitation and irritability are frequent

4. Stage: Advanced stage of the disease

2. Stage: Early symptoms of already defined disease

Complete dependency on caregivers
Speaking extremely poor with the possibility of complete drop
Frequent aggressivity or extreme apathy
Strong decline in muscular strength-inability to stand and walkStrong decline in immunity and increased incidence of acute infections(pneumonia or other infective diseases), which are often fatal*According to other literature there are seven stages of AD

Clear decrease in ability to learn new content
Marked decrease in memory, particularly new data
Drop in spectrum of used words and fluidity of speaking

3. Stage: Decline in ability in dealing with common daily jobs
Reduced ability to recollect words necessary for conversation
Decline in reading and writing ability
Drop in motor activity
Decreased short-term memory
Frequent inability for recognition of friends and members of household
Frequent episodes of agitation, aggressiveness and tearfulness
Urinary incontinence may occur_ 70 _Glycative Stress Researchleading to the accumulation of Aß peptide. The 240-kb geneencoding APP contains 18 exons and is located on the longarm of chromosome 21. APP is predominantly expressed in
the vicinity of synapses and plays an essential role in synapse
formation and repair ( Figs. 3, 4 ) 14 -17).

NFTs are formed intracellularly from hyperphosphorylated
tau protein bound to microtubules. The activation of GSK-3 by
RAGE has a crucial role in NFT formation. Following these
events, microtubules are destabilised and undergo disintegration,
thereby reducing their transport function ( Fig. 5 ).

Aß protein is a polyfunctional molecule that protects cells
from oxidative stress and is involved in cholesterol transport
regulation. In AD, the production of Aß protein is markedly
elevated, particularly in SPs. SPs are an average of 50 µm(range: 10~160 µm) and are composed of helical filaments ofindividual Aß monomers. Located in the vicinity of SPs aremany small astrocytes (10~20 µm with 20~30 µm projections)and microglia, in addition to other proteins and metallic ions
( Fe3+ and Fe2+ ).

The interaction between RAGE and AGEs, particularly in
conjunction with N ε-(carboxymethyl)-lysine (CML), strongly
induces protein kinase C (PKC), NADPH (reduced form of
nicotinamide adenine dinucleotide phosphate) oxidase, andIκB (IKK) activation, leading to IκB protein (NF-κB blocker)
degradation and liberation, and activation of transcription
factor NF-κB.Thus, AD is also characterized a NF-κB cascadewith the induction of strong atherogenic response 11, 15 ).

Fig. 1. Schematic diagram of a neuronal cell and amyloid plaques in AD.

AD, Alzheimer's disease; EO-fAD, early onset-familial AD; LOAD, late onset AD; Aß, amyloid beta (reductant); AGE, advanced glycation end product;
RAGE, receptor for AGE; APP, amyloid precursor protein; LDL, low-density lipoprotein; LDLR, LDL receptor; MCP, monocyte chemotactic protein; CSF,
colony-stimulating factor; ApoE, apolipoprotein E. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or activity of the appropriate
symbol next to the arrow.

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AGEs in Alzheimer's disease

Fig. 2. Schematic diagram of the glycation (nonenzymatic glycosylation) of amyloid beta (Aß)

AD, Alzheimer's disease; c.m., cell membrane; i.c.s., intra cellular space; e.c.s., extra cellular space; AA, amino acid; Aß, amyloid beta; AGEs, advanced
glycation end products; RAGE, receptor for AGE; APP, amyloid precursor protein; ROS, reactive oxygen species; 3DG, 3-deoxyglucosone; GO, glyoxal;
MGO, methylglyoxal; GA, glyceraldehyde; FL, N ε-fructosyl-lysine; CML, N ε-(carboxymethyl)-lysine; CEL, N ε-carboxy(ethyl)-lysine; GOLD, glyoxallysine dimer; MOLD, methyl-glyoxal-lysine dimer; EA, erythronic acid; GI, glycemic index. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of
the quantity or activity of the appropriate symbol next to the arrow.

_ 72 _Glycative Stress Research

Fig. 3. Schematic diagram of the molecular events related to AD (early-onset genetic form of AD).

AD, Alzheimer's disease; plasma m., plasma membrane; i.c.s., intra cellular space; e.c.s., extra cellular space; glu., glucose; AA, amino acid; Aß, amyloid
beta; AGEs, advanced glycation end products; RAGE, receptor for AGE; APP, amyloid precursor protein; TNF, tumor necrosis factor; NFT, neurofibrillarytangle; ROS, reactive oxygen species; NF-κB, nuclear factor kappa-B; PDGF, platelet-derived growth factor; VCAM, vascular cell adhesion molecule; ICAM,
intercellular adhesion molecule; MCP, monocyte chemoattractant protein; M-CSF, macrophage colony-stimulating factor; COX, cyclooxygenase; MMP,
matrix metalloproteinase; IL, interleukin; PK, protein kinase; MAPK, mitogen-activated protein kinase; GSK, glycogen synthase kinase; NADPH, reduced
form of nicotinamide adenine dinucleotide phosphate; JNK. c-jun N- terminal kinase; BCL, B-cell lymphoma; MAC, mitochondrial apoptosis-induced
channel. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or activity of the appropriate symbol next to the arrow.

_ 73 _

AGEs in Alzheimer's disease

Fig. 4. Schematic diagram of synaptic events potentially associated with the onset of AD

Mutations in ADAM 10 (in LOAD) lead to reduced α-secretase activity. Mutations in ApoE (in LOAD) induce poor binding and degradation of Aß inastroglia. RAGE mediates Aß translocation from the extracellular to intracellular space.
AD, Alzheimer's disease; LOAD, late onset AD; T, neurotoxic; R, receptor; M, mitochondria; Aß, amyloid beta; AGEs, advanced glycation end
products; RAGE, receptor for AGE; APP, amyloid precursor protein; glu., glucose; syn., synthesis; ATP, adenosine triphosphate; Ach, acetylcholine;
LDL, low-density lipoprotein; LDLR, LDL receptor; ROS, reactive oxygen species; PKC, protein kinase C; GSK, glycogen synthase kinase; MCP,
monocyte chemoattractant protein; ApoE, apolipoprotein E. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or activity of
the appropriate symbol next to the arrow.

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Fig. 5. Cascade of events induced by GSK-3 activation.

AD, Alzheimer's disease; Aß, amyloid beta; AGEs, advanced glycation end products; RAGE, receptor for AGE; GSK, glycogensynthase kinase; PK, protein kinase; TNF, tumor necrosis factor; CNS, central nervous system; NFT, neurofibrillary tangle; NF -κ
B, nuclear factor kappa-B. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or activity of the appropriate
symbol next to the arrow.

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AGEs in Alzheimer's disease

Glycation of β amyloid

The involvement of the nonenzymatic glycation of Aßand the generation of Aß -AGE compounds in the onset anddevelopment of AD, has been confirmed in a number ofrecent investigations 11, 14, 18 ) . Glycation is considered to confer
stability and increase the half-life of proteins, including Aßprotein. AD patients display marked elevation of the glycation
process in the brain. In addition, a dramatic increase in early
glycation Amadori products and AGEs is also typicallyobserved 8, 14, 18 ) .
Many scientists speculate that AGEs are strongly
associated with the onset and course of AD. In fact, nearly
all recently proposed theories concerning the etiology andcourse of AD involve the interference of AGEs compounds
at different stages of the underlying pathophysiologic events.
In particular, the role of AGEs compounds in the function of
RAGE has attracted attention. In addition, the importance oftau protein, ß and γ secretases, APP, GSK-3, microtubulebased axon transport, and neuronal cortical, hippocampal, andamygdaloidal destruction in AD has also been proposed.
Shuvaev et al. 18) investigated glycation levels in the
cerebrospinal fluid (CSF ) and plasma of AD patients andthat the glycation rate corresponds to the severity of AD. In
AD brains, the level of AGEs is significantly higher than thatfound in normal brains 24) . Srikanth et al. 8) also proposed that
RAGE and AGEs have important roles in AD pathogenesis.
Although the accumulation of AGEs in cells and tissues is anormal sign of ageing, AGE levels are significantly increasedin AD. AGEs are also components of SPs and NFTs andplay a role in the cross-linking of proteins, oxidative stress,and deterioration of neurons 14) . Fawver et al. 14) found thatglycation and accumulation of SPs is accelerated in the brainsof patients with Down syndrome, and also speculated thatglycation influences the pathology and progression of AD 20) .
Li et al. 11) analysed the glycation process in AD brains,particularly Aß-AGE complex generation, Aß and Aß-AGE
interaction with RAGE, and GSK-3 signal cascade activation,and found that incubation of Aß peptides with methylglyoxal
induced the production of Aß-AGE, which, induced theformation of large lesions in hippocampal neurons. Based onthese findings, GSK-3 activation, PKB (Akt) blockade, andtau protein hyperphosphorylation was proposed to induce
NFTs formation and microtubular destabilisation, leading todecreased microtubular transport. Thus, Aß and Aß-AGE arehighly neurotoxic compounds whose accumulation appears tobe critical for the onset and progression of AD 17) .
AGEs are found at high concentrations in SPs, which arelocated near astrocytes and microglia plasma membranes, andRAGE. RAGE activation induces a biochemical cascade ofharmful molecular events that cause functional aberrations,followed by the destruction and death of cells. Together,
these events induce the global destruction of important brain
functions 19, 25 ) .
The participation of AGEs in AD pathogenesis has been
proposed by a number of investigators. For example, Takeuchi
et al. 26) speculated that AGEs are involved in the onset andcourse of AD as AGEs were found in both SP and NFT
lesions. Glyceraldehyde-combined AGE (Glycer-AGE) has
a special importance in AD pathogenesis 14, 20, 24, 25 - 32 ). The
role of reactive oxygen species (ROS) in AD etiology as also

been proposed. In addition, Sato et al. 27 ) also proposed that
AGEs and RAGE have important roles in the pathogenesisof AD. These researchers identified that AGE-2 derived
from glyceraldehyde is found in the hippocampus andparahippocampal gyrus of AD patients 33) .
Using specific antibodies against AGEs, Yan et al. 28 )established that AGEs are closely associated with paired
helical filaments in NFTs in the neurons of patients with thesporadic form of AD. In these neurons, signs of oxidative
stress, which is known to play a role in neuronal destruction,
were also observed 20 - 25 ) . These findings indicate that tau
protein and Aß peptide in environments rich in aldose easily
enter the glycation process, leading to Schiff base, Amadori
product, and AGEs formation, which may be critical forgenesis of AD 34 ) .
The close connection between AGE accumulation
and NFT generation was also demonstrated by Luth et al 16 ),who analysed the relationship between neuronal AGEs
accumulation, NF T formation, and cell death. Histochemical
analyses revealed that RAGE stimulation induces GSK-3,
leading to the hyperphosphorylation and fragmentation of
tau protein, and its disassociation with microtubules. AGE
complexes bind tau protein fragments and form NFT particles
with a high AGE content. These findings also emphasize theclose association between AGE-positive neurons and AD
severity 22) .
Takeuchi et al. 29) used an immunohistochemical-based
approach to demonstrate that SP and NFTs contain a highproportion of AGEs. In addition, these authors speculated that
diabetes mellitus is a strong risk factor for AD. In addition,
the interaction of AGEs derived from glyceraldehyde with
RAGE, and the role of oxidative stress in the development andprogression of AD was also proposed 32, 35, 36 ) .
The importance of GSK-3 in the genesis and progression
AD has also been proposed 31). In particular, the kinase GSK3ß has been shown to promote the agglomeration of tau protein(paired helical filament -tau component of NFTs. The GSK3ß /phosphatidilinozitol-3 P13/Akt and Aß /AGE/RAGE/Akt /GSK-3 signaling cascades were confirmed to play a role in thisprocess 37).
Two mutations in the ADAM 10 gene, located on the longarm of chr.15 (chr.15q22) have recently been identified (Tanzi
and Suh, 2013). These mutations, Q170H and R181G, impair
the α secretase activity of ADAM 10, leading to reduced
cleavage of the Aß fragment from APP. In normal cells(without AD changes), following the cleavage of APP by ß andγ secretases, complete Aß peptide is released into synapses.
Thus, these mutations in ADAM 10 have an important role inthe development of LOAD ( Fig. 6 ) 38).
In a great number of LOAD there is a dominance ofapolipoprotein E (APOE), especially allele ApoE ε 4 - 40-80%.
ApoE ε 4 is important for directing amyloid beta peptide tosynapses and its low binding and transport to astrocytes where
it is insufficiently degraded. Thus, its Aß concentration iselevated. The toxicity of Aß rises, and the result is exacerbatedsynapse loss around the plaques 39).
TREM2 gene (mutations associated with a 3 to 5-foldgreater risk for AD). It is important for controlling the quantity_ 76 _Glycative Stress Researchof Aß in the brain. It codes one microglial receptor-triggering
receptor expressed on myeloid cells; chromosome 6p21.1;
anti-inflammatory role in the brain 40) .
A potential connection between the level of free iron(ferrous iron-and non-transferrin bound iron [NBTI]) and AD
has been proposed 24). The H2O2-induced oxidation of freeiron through the Fenton reaction generates ferric iron ( Fe3 + ),hydroxyl ion, and ( - OH) hydroxyl radical (*OH), which isa strong oxidant and is especially toxic for neurons. RAGE
/Aß /Aß-AGE interaction impairs astrocyte iron transport,
leading to iron accumulation, particularly ferrous iron (Fe 2 + )14, 20, 25, 26 -31).

Mitochondrial dysfunction

In addition to their involvement in SP formation,
Aß peptides have strong toxic effects on mitochondria (Fig. 7 ).
Aß affects nearly all mitochondrial structures and functions,
including the ETC, Krebs cycle, membranes, DNA, proteins,
receptors, and transmembrane channels. Aß induces the
production ROS that disrupt the ETC, and activation of thetranscription factor JNK, leading to expression of the apoptotic
genes Bax and MAC, which encode channels that control
Cyt-c and Smac efflux from mitochondria into the cytosol.
This efflux leads to caspase activation and induction of theapoptotic cascade in astrocytes and neurons ( Fig. 7 ).

Fig. 6. Involvement of two mutations in the ADAM 10 gene on late-onset AD (LOAD).

AD, Alzheimer's disease; i.c.s., intra cellular space; e.c.s., extra cellular space; N, nucleus; Aß, amyloid beta; AGEs, advanced glycation end products; RAGE,
receptor for AGE; APP, amyloid precursor protein; AICD, APP intracellular domain; sAPPα, secreted ectodomain α; sAPPß, secreted ectodomain ß; CTF, C
terminál fragment; SPs, senile plaques. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or activity of the appropriate symbol next
to the arrow.

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AGEs in Alzheimer's disease

Fig. 7. Schematic representation of the mitochondrial hypothesis in the Alzheimer’s cascade.

R, receptor; T, neurotoxic; Q, coenzyme Q10; mit., mitochondria; AD, Alzheimer's disease; i.c.s., intra cellular space; e.c.s., extra cellular space; Aß, amyloid
beta;ATP, adenosine triphosphate; ADP, adenosine diphosphate; mit., mitochondoria; TOM, translocase of the outer mit. membrane; TIM, translocase of theinner mit. membrane; OMM, outer mit. membrane; IMM, inner mit. membrane; IMS, intermembrane space; SOD, superoxide dismutase; PTP, permeability
transition pore; ANT, adenine nucleotide translocase; VDCC, voltage-dependent calcium channel; VDAC, voltage-dependent anion-selective channel; JNK,
c-Jun N-terminal kinase; MAC, mit. apoptosis induced channel; Smac, second mitochondrion-derived activator of caspase;
AGEs, advanced glycation end products; RAGE, receptor for AGE; APP, amyloid precursor protein; ROS, reactive oxygen species; 3DG, 3-deoxyglucosone;GO, glyoxal; MGO, methylglyoxal; GA, glyceraldehyde; FL, N ε-fructosyl-lysine; CML, N ε-(carboxymethyl)-lysine; CEL, N ε-carboxy(ethyl)-lysine; GOLD,glyoxal-lysine dimer; MOLD, methyl-glyoxal-lysine dimer; EA, erythronic acid; PK, protein kinase; MAPK, mitogen-activated protein kinase; GSK, glycogensynthase kinase;NAD, nicotinamide adenine dinucleotide; NADPH, reduced form of NAD phosphate; BCL, B-cell lymphoma; Cyt-c, cytochrome C; CI-CV, mitochondrial
respiratory chain complexes; ABAD, Aß peptide-binding alcohol dehydrogenase; DNA, deoxyribonucleic acid; Mcl-1, induced myeloid leukemia celldifferentiation protein; Bcl, B-cell lymphoma; Bcl-w, Bcl-x(L), antiapoptotic genes; Bax; Bcl-2-associated X protein (apoptotic gene); Bak, BCL2-antagonist/killer protein; LH, lipid hydroxylated = PUFA, polyunsaturated fatty acid. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or
activity of the appropriate symbol next to the arrow. Horizontal red arrows ( → ) indicate electrons moving through the electron transport chain. The top of theblack arrow ( → ) indicates the molecular attack.

_ 78 _Glycative Stress Research

Treatment of AD

Elevated intake of AGEs in foods or the inadequate
processing of AGEs are suggested to leads to earlier onset
of AD and a more rapid course, particularly individuals withgenetic predisposition ( Figs. 8 and 10 ) 41- 43).

Although the direct cause of AD remains unclear, several
theories, including those described above, have been proposed.
Understanding the underlying cause(s) of AD is necessary
for the development of preventative measures and effective
therapies. Currently, two groups of medications are available:cholinesterase inhibitors and antagonists of N-methyl-Daspartate (NMDA) receptors ( Table 3 ). The former group
includes donepezil hydrochloride (Aricept), rivastigmine(Exelon), and galantamine hydrobromide (Reminyl), while
the latter group includes memantine (Ebixa). Cholinesterase
inhibitors function by blocking acetylcholine (Ach) esterase,
which is an Ach breaker. The crucial effects of memantine
are connected with NMDA receptors (NMDAR, N-methyl-D-aspartate receptor, glutamate receptor). By binding to
NMDAR, memantine protects the brain cells from harmful
effects of, in AD elevated concentrations of released glutamate(N-Methyl-D-aspartate, NMDA) from damaged brain cells.
Memantine is the glutamate antagonist and by binding to
NMDAR suppresses the harmful glutamate effect.Chemistryname for memantine is 1-amino-3,5-dimethyladamantane
hydrochloride 32-35, 39-41).
A number of other compounds with possible beneficial
effects for AD treatment have been evaluated, including
antioxidants, AGE breakers, RAGE blockers, and antiglycation
compounds ( Fig. 9 ). In addition, several novel compounds
are under experimental and clinical investigation, and include
alagebrium (ALT-711), aminoguanidine, 4,5-dimethyl-3phenacylthiazolium chloride (DPTC), benfotiamine, tiamine,and piridoxamine. The analysis of the efficacy of thesecompounds for AD therapy, and other methods of AD therapy,
are beyond the scope of this study, but have been discussed
elsewhere ( Figs. 9-11, Table 3 ) 34 -37,41-43) .

Fig. 8. Exogenous AGEs and their influence on the progression of Alzheimer's disease.

Consumption of low quality, inadequately processed foods leads to earlier and a more rapid onset and progression of this deteriorative disease in genetically
predisposed individuals.
AD, Alzheimer's disease; Aß, amyloid beta; AGEs, advanced glycation end products; dAGEs, dietary AGEs; RAGE, receptor for AGE; APP, amyloid
precursor protein; NFT, neurofibrillary tangle; HMG1, high-mobility group protein 1; ROS, reactive oxygen species; PK, protein kinase; MAPK, mitogenactivated protein kinase; GSK, glycogen synthase kinase; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor
kappa-B; PDGF, platelet-derived growth factor; VCAM, vascular cell adhesion molecule; ICAM, intercellular adhesion molecule; MCP, monocyte
chemoattractant protein; TNF, tumor necrosis factor; IL, interleukin. The red arrow indicates the increase ( ↑ ) or decrease ( ↓ ) of the quantity or activity of
the appropriate symbol next to the arrow.

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AGEs in Alzheimer's disease

Fig. 9. AD therapies.

Inhibitors and breakers of previously formed AGEs (left). Antioxidants and free radical (ROS) scavengers are likely involved in theonset and pathophysiology of AGEs (right).
* included in AD therapy, AD, Alzheimer's disease; ROS, reactive oxygen species; AGEs, advanced glycation end products; Aß, amyloid
beta; dAGEs, dietary AGEs; RAGE, receptor for AGE; CML, N ε-(carboxymethyl)-lysine; AG, aminoguanidine; DPTC, 4, 5-dimethyl3-phenacylthiazolium chloride; ASA, acetylsalicylic acid; LA, lipoic acid; SOD, superoxide dismutase.

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Fig. 10. Causes of higher (+) and lower (-) AGE generation in food.

Food processing temperatures above 230°C (446oF) are critical for subsequent rise in dAGEs (d=dietary) formation. AGEs,
advanced glycation end products; CML, N ε-(carboxymethyl)-lysine.

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AGEs in Alzheimer's disease

Table 3. Important medications for AD.
Drug class

Compound

Cholinesterase inhibitors

Aricept (donepezil hydrochloride)
Exelon (rivastigmine)
Reminyl (galantamine)*

NMDA receptor antagonists

Ebixa (memantine)†

NMDA, N-methyl-D-aspartate.

Conclusion

The continued increase in the incidence of dementias,
particularly AD, as life expectancy concomitantly rises is
becoming a significant problem worldwide. As the incidenceof AD is now greater than 10% in most populations, the costs
associated with the care and treatment of affected individuals
places an enormous financial burden on individual families,
the health sector, as well as the overall society. Although theexact cause of AD remains elusive, the potential role of AGEs
in the development and progression of AD has been recently
recognized. This finding has prompted numerous biochemical,
epidemiologic, and clinical studies aimed at deciphering theroles of AGEs in AD in the hope of developing an effective
therapy in the near future.

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Acknowledgements

Part of this research was presented at the 25th Summer
Stroke School “Healthy Lifestyle and Prevention of Stroke” onJune 10, 2014, at Dubrovnik, Croatia.

Conflicts of interest statement

The author has no conflicts of interest related to this study
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