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Curr Med Chem. 2011 ; 18(22): 33063313.

The Aged Garlic Extract(AGE) and One of its Active

Ingredients S-Allyl-L-Cysteine (SAC) as Potential Preventive and
Therapeutic Agents for Alzheimers Disease (AD)
B. Ray1, N.B. Chauhan2, and D.K. Lahiri1,3,*
1Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Department of
Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
2Jesse Brown VA Medical Center Chicago, Department of Pediatrics and Department of Anatomy
& Cell Biology, University of Illinois at Chicago, IL 60612, USA
3Department of Medical and Molecular Genetics, Indiana University School of Medicine,
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Indianapolis, IN 46202, USA

Abstract
Alzheimers disease (AD) is the most common form of dementia in the older people and 6th
leading cause of death in the United States. Deposition of amyloid-beta (A) plaques,
hyperphosphorylation of microtubule associated protein tau (MAPT), neuroinflammation and
cholinergic neuron loss are the major hallmarks of AD. Deposition of A peptides, which takes
place years before the clinical onset of the disease can trigger hyperphophorylation of tau proteins
and neuroinflammation, and the latter is thought to be primarily involved in neuronal and synaptic
damage seen in AD. To date, four cholinesterase inhibitors or ChEI (tacrine, rivastigmine,
donepezil and galantamine) and a partial NMDA receptor antagonist (memantine) are the only
approved treatment options for AD. However, these drugs fail to completely cure the disease,
which warrants a search for newer class of targets that would eventually lead to effective drugs for
the treatment of AD. In addition to selected pharmacological agents, botanical and medicinal plant
extracts are also being investigated. Apart from its culinary use, garlic (Allium sativum) is being
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used to treat several ailments like cancer and diabetes. Herein we have discussed the effects of a
specific Aged Garlic Extract (AGE) and one of its active ingredients, S-allyl-L-cysteine (SAC)
in restricting several pathological cascades related to the synaptic degeneration and
neuroinflammatory pathways associated with AD. Thus, based on the reported positive
preliminary results reviewed herein, further research is required to develop the full potential of
AGE and/or SAC into an effective preventative strategy for AD.

Keywords
Aged garlic extract; aging; amyloid; Alzheimers disease; botanicals; brain; dietary; medicinals;
neuroinflammation; nutraceuticals; nutrition; synapse; pleiotropic; resveratrol; tau; therapeutics

2011 Bentham Science Publishers Ltd.

*
Address correspondence to this author at the Department of Psychiatry, Indiana University School of Medicine, 791Union Drive,
Indianapolis IN 46202 USA; Tel: 317-274-2706; Fax: 317-274-1365; dlahiri@iupui.edu.
 Ray et al. Page 2

1. INTRODUCTION
Alzheimers disease (AD) is the most common form of dementia affecting elderly
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populations all over the globe. Over 5.4 million people in the United States are diagnosed
with AD and this number will triple by mid- century if definite curative or restrictive
therapies are not developed[1]. Neuropathologically, deposition of amyloid (A) peptides
in the brain parenchyma, hyperphosphorylation of microtubule associated protein tau
(MAPT) and loss of cholinergic neurons comprise the major hallmarks of AD. It is believed
that deposited A peptides trigger a series of inflammatory reactions including activation of
microglia, generation of reactive oxygen species (ROS) and cytochemokines result in
widespread neuronal loss [2]. To date, four cholinesterase inhibitors (ChEI; tacrine,
rivastigmine, donepezil and galantamine) and a partial NMDA receptor antagonist
(memantine) are the only treatment options for AD. Although these drugs can provide some
symptomatic relief, they fail to cure or restrict the disease progression. In this context,
clinical trials with new drugs aiming to decrease A production have been conducted.
Unfortunately, some of these trials were halted because of serious adverse effects including
cancer [3]. Moreover, these drugs primarily target a single pathological pathway such as A
precursor protein (APP) processing. It is indicated that deposition of A peptides as diffuse
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plaques appear much earlier in the disease process and it is possible that people may remain
cognitively intact for decades[4]. Neuroinflammation may be a key player responsible for
the clinical onset of AD[5]. Since AD has multifactorial etiopathogenesis, such as neuritic
plaques, neurofibirillary tangles, severe neuroinflammation, glutamate induced
excitotoxicity, defective A breakdown, we hypothesize that an agent effective in
modulating multiple pathological pathways could be an appropriate therapeutic agent in
preventing and restricting AD progression. Although sequence of these events is poorly
understood, they result in widespread neuronal and synaptic loss.

In addition to pharmacological agents, botanical and medicinal plant extracts are also being
investigated. Some of these studies are based on dietary and epidemiological studies,
including incidence and prevalence of AD in different cultures and countries. For example, a
large epidemiological study had depicted a significant (~4.4-fold) less incidence of AD in
Indian elderly when compared with a reference American populace[6]. Another
epidemiological study did not observe any association between AD and APOE 4 in an
elderly cohort in Nigeria. However, the latter was strongly associated with AD in African
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American populations[7]. These findings indicate a strong environmental contribution in the

development of AD, which may include dietary factors. In this context, Mediterranean diets
are believed to protect against the development of AD[8]. Resveratrol (a polyphenol present
in fruits and red wine) increases cerebral blood flow in young adults [9]. Curcumin (a
polyphenol present in turmeric and curry powder) was shown to have protective or curative
roles in AD models [2]. However, curcumin failed to exert significant beneficial effects in
clinical settings[10], which can be attributed to its poor bioavailability and rapid bio-
transformation[11]. In this context, we have observed increased bioavailability and
significant neuroprotective properties of a nanoformulation of curcumin (NanoCurc) in
vivo as well as in neuronal cells [11]. We studied further to evaluate potential beneficial
roles of other naturally occurring compounds in the context of neurodegenerative disorders,

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such as AD, and observed significant neuroprotective and synaptopreservative properties of

garlic derived compounds in animal and cell culture models [12]. In this review, we will
discuss pleiotropic properties of garlic components in modifying several pathological
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cascades involved in AD.

Apart from culinary purposes, garlic (Allium sativum) is being used to treat different
ailments such as cardiovascular [13], gastrointestinal [14], hematological [15] and as cancer
[16]. Recent studies have demonstrated beneficial effects of Aged Garlic Extract (AGE)
and one of its active ingredients S-Allyl-L-Cysteine (SAC) in AD models [12, 17]. In these
studies AGE and SAC treatments not only decreased A loads in APP-transgenic (Tg) mice,
but also ameliorated tau pathology and increased levels of synaptic protein markers versus
vehicle treated mice. Previous studies also demonstrated potent antioxidant action of AGE
[18].

2. ALZHEIMERS DISEASE (AD) - BASIC PATHOLOGY AND

NEUROCHEMISTRY
2.1. A Deposition
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A peptide is a generated from APP by sequential enzymatic cleavage of - and secretases.

APP, which is encoded by a long gene localized in human chromosome 21, is a large (695
770 amino acids) glycosylated transmembrane protein. Apart from mammalian APP, two
other non-mammalian homologous proteins were also identified which are appl (present in
Drosophila melanogaster) and apl-1 (present in the worm Caenorhabditis elegans) [1920].
APP is first cleaved by secretase (also known as BACE-1) to produce sAPP (596 amino
acids for APP 695 isoform) and a C-terminal 99 amino acid containing fragment (C99)[21].
In the final step of processing, C99 is cleaved by secretase to produce A peptides,
containing 3943 amino acids residue [22]. The A peptide with 40 amino acids (A40) is
abundantly produced in this process and considered as less pathogenic. However, the A
peptide with 42 amino acids residue (A42), although produced in lower quantities, is
fibrilar in nature and can potentially form aggregates [2324]. In addition to aggregated A,
soluble oligomeric A species are neurotoxic, and the brain load of the latter was found to
be positively correlated with the clinical symptoms of AD [2526]. It is believed that A
deposition can also trigger hyperphosphorylation of tau and neuroinflammation including
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generation of ROS.

2.2. Hyperphosphorylation of Microtubule Associated Protein Tau (MAPT) (Tauopathies)-

Evidence from Animal and Clinical Studies
MAPT or Tau is a microtubular protein found in neurons and coded by a gene located at
chromosome 17 [27]. One of the primary functions of tau is to provide structural stability of
microtubule by interacting with tubulin, another structural protein of the cell [28]. Tau is a
phosphoprotein, and hyperphosphorylation can prevent binding of tau with tubulin, hence
destabilize axonal structures. Phosphorylation at Ser and/or Thr residues at different
positions (such as Ser 262, Thr 231, Ser 235) of tau protein is considered as the major forms
of phosphorylation and observed in neurodegenerative disorders including AD [29]. Several
protein kinases including glycogen synthase kinase-3 (GSK-3) and cyclin dependent

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kinase-5 (cdk-5) can phosphorylate tau protein [30]. Postmortem AD brain revealed 3-4-fold
more hyperphosphorylation of tau protein versus post mortem non-AD brain tissue [31]. To
date, it is not completely clear whether or not deposition of A causes tau
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hyperphosphorylation. Intracerebral infusion of A peptides in Tg mice models induced

tauopathies [32]. Further, intracerebral infusion of deposited A peptides collected from
aged APP-Tg mice to young tau-Tg mice resulted in an increase in tau pathology in the
brain of the injected mice [33]. In a triple transgenic mouse model (APP, presenilin-1 and
tau), A deposition was observed before the appearance of tangle pathology [34].

Beyond AD and in a clinical study, we also observed increased levels of CSF-phosphotau in

normal pressure hydrocephalus (NPH) patients suffering for more than one year [35].
Cardinal pathology of NPH involves disruption of CSF hemodynamics, which may result in
increased A deposition [35]. However, tau pathology was not observed in the postmortem
brain samples of patients suffered in a rare disease, hereditary cerebral hemorrhage with
amyloidosis of Dutch type (HCHWA-Dutch), which also showed a considerable amount of
A burden [36]. Moreover, a growing body of evidence suggests a link between
hyperphosphorylation of tau in diabetes. Brain tissues of streptozotocin induced diabetic
rats revealed decreased levels of insulin in the brain due to altered transport of insulin
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across the blood brain barrier (BBB) [37]. Further, GSK-3, a prime enzyme responsible for
pathological phosphorylation of tau can be inactivated by insulin [38]. Thus apart from AD,
other disorders such as NPH, diabetes can induce hyperphosphorylation of tau.

2.3. Neuroinflammation
As stated earlier, neuroinflammation is believed to play a central role in the clinical onset of
AD[5]. This is consistent with the observations that deposited A can activate microglia,
which produces cytochemokines (such as TNF, ILs) and result in neuroinflammation.
Further, ROS, nuclear factor kappa beta (NFB), peroxisome proliferators-activated
receptor- (PPAR), apolipoprotein E (APOE) are also thought to play important roles in
neuroinflammation associated with AD (for review see [2]). Neuroinflammation can be an
important cause for widespread neuronal damage observed in AD, especially cholinergic
neurons in basal forebrain are more susceptible for degeneration [39].

3. CHEMICAL COMPOUNDS EXTRACTED FROM GARLIC

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Garlic consists of several sulfur containing ingredients and alliin (S-allyl cysteine sulfoxide)
is the major one. Alliin undergoes several chemical transformations to generate a series of
other sulfur compounds such as allyl thiosulfinate, allicin, allyl methyl thiosulfinate, allyl
propenyl thiosulfinate, diallyl disulfide, and allyl methyl sulfide [40]. SAC is an important
component of garlic which is produced by hydrolysis from -glutamyl-S-allyl cysteine [40].
Some sulfur containing garlic compounds are sparely water soluble and upon ingestion can
also cause adverse effects in humans[12]. AGE is prepared by soaking garlic in ethanol-
water mixture for 20 months, which removes irritant compounds from garlic and solubilize
some of the insoluble compounds [41]. SAC is one of the active ingredients of AGE.
Previous report has proposed greater safety and efficacy of AGE than raw garlic as a
therapeutic agent [42].

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4. POTENTIAL ROLES OF AGE AND SAC IN AMELIORATING AD-LIKE

PATHOLOGY
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4.1. A Related Pathology

AGE and SAC were observed to possess potential anti-amyloidogenic properties both in
vitro and in vivo studies. Previous research has demonstrated protection of cellular structures
by AGE from A- mediated damage [4344]. Mechanistically, SAC was shown to have A
disaggregation property in vitro [45]. In an AD animal model, four months of independent
treatments of AGE and SAC resulted in a significant decrease of both A load and numbers
of A plaques in the brain of APP-Tg mice (Tg-2576) versus non-treated Tg mice controls
[17]. In addition to levels of A peptides, brain lysate of the animals from the above study
was analyzed in Western immunoblotting to measure intracellular APP. Notably, we
observed a significant decrease in the levels of intracellular APP in AGE-treated APP-Tg
mice versus untreated Tg mice (Ray and Lahiri unpublished). The exact mechanism of AGE
and SAC in modulating APP levels or processing is still not properly elucidated and could
be mediated through NFB (discussed later).

Apart from that, it was also observed that SAC can prevent A-mediated hippocampal
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neurodegeneration by attenuating endoplasmic reticulum (ER) stress [46]. Another

important aspect of AGE and SACs mechanism is their ability in inhibiting the activation of
caspase 3[47]. Deposited A can increase the level of activated caspase 3 [48], which was
also observed in APP-Tg mice brain versus wild type mice. It was also observed that
activation of caspase 3 can lead to decreased synaptic function and postsynaptic density
[49]. We have observed significant increase in the levels of pre-synaptic proteins SNAP25
and synaptophysin in brains of APP-Tg mice treated with either AGE or SAC versus non-
treated APP-Tg mice [12]. Further, we have observed decreased levels of cleaved caspase 3,
which indicates inhibition of the caspase 3 activity in AGE-treated APP-Tg mice brain
samples versus untreated Tg mice (data not shown).

4.2. AD, Diabetes Mellitus, Cholesterol and the Role of Insulin

Based on a variety of current research results, a strong positive correlation between diabetes
mellitus and AD has been proposed. Insulin in the brain can display growth factor like
functions [50]. Further, insulin increases the expression of choline acetyl transferase (ChAT)
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in cholinergic neurons of basal forebrain [51]. In addition, insulin degrading enzyme (IDE),
which catalyzes insulin also takes part in breaking down of A peptides in the brain [52].
Hence diabetes mellitus, characterized by reduced production or peripheral resistance of
insulin may lead to the development of AD. Interestingly, garlic can increase insulin
secretion from pancreatic cells, i.e. considered as an insulin secretagogue [53].
Secretagogues, which are medicines that stimulate the beta cell to secrete insulin, include the
sulfonylureas and glinides. In experimental settings one of the garlic derived compounds S-
Allyl-L-cysteine sulfoxide (SACS) was shown to ameliorate symptoms of diabetic rats, and
this action of SACS was comparable to glibenclamide, a known anti-diabetic agent [54].
Another important aspect of AGEs and SACs beneficial roles in A-related pathology is
by augmenting cardiovascular health. Epidemiological and clinical studies have documented
that cardiovascular lesions are common in AD and are also potential risk factors [5556].

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Hypercholesterolemia, the most important causative factor for cardiovascular pathology,

was shown to enhance brain A accumulation [57]. Refolo et al. demonstrated an alteration
in APP processing towards amyloidogenic pathway by cholesterol in Tg mice model [58].
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Further, radio imaging study has documented that higher serum cholesterol level is
associated with increases frequency of APOE 4 alleles, one of the well known risk factors
for AD [59]. Interestingly, garlic and garlic derived compounds were shown to have potent
antilipidemic properties in term of inhibiting cholesterol synthesis [6062]. Several
mechanisms of garlic and its components lipid lowering properties were proposed including
inhibition of the rate limiting enzyme of cholesterol biosynthesis, HMGCoA-reductase [63].

The summary of potential effects of AGE and SAC in ameliorating A-related pathology is
illustrated in Fig. (2).

4.3. Potential Roles of AGE and SAC in Ameliorating Tauopathies

In the molecular sequel related to the pathogenesis of AD, hyperphosphorylation of tau
proteins is believed to follow A deposition and to form neurofibrillary tangles. Certain
garlic compounds effects in ameliorating tau pathology in preclinical settings are
encouraging. Working with APP-Tg mice, Chauhan observed a decreased level of tau
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phosphorylation in APP-Tg mice by independent treatments of AGE, SAC and diallyl

disulfide (DADS), another compound present in garlic. Mechanistically, the decreased level
of tau phosphorylation was most likely due to decreasing the activity of GSK-3 by garlic
compounds [17]. No change in the levels of Cdk5 was observed in the treated animals
versus controls. As discussed, deposition of A peptides can induce hyperphosphorylation of
tau protein, AGE or SACs anti-amyloid properties can also be responsible for preventing
hyperphosphorylation of tau. Interestingly, insulin secretagogue action of garlic compounds
can increase the brain levels of insulin and insulin like growth factor (IGF), which can
decrease brain A burden and inhibit the activation of GSK-3 and can potentially prevent
tau phosphorylation. Further, studies revealed an increased level of tau phosphorylation both
in cortex and hippocampus of rats that were fed with high cholesterol containing diet for a
prolog period of time (6 months) [64]. In AD patients, increased in the levels of CSF-
phosphotau is considered as one of the diagnostic criteria [65]. It was observed that 14-
weeks treatment with an HMGCoA- reductase inhibitor (simvastatin) decreased the levels of
CSF-phosphotau in hyperlipidemic patients with dementia [66], and this can be attributed as
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an indirect evidence that hyperlipidemia can potentially cause hyper-phosphorylation of tau

proteins. Due to antilipidemic properties, garlic compounds can play an important role in
ameliorating tauopathies. In addition, several studies have shown that inflammation can
induce tau pathology. Induction of microglial activation by lipopolysaccharide (LPS) was
shown to increase tauopathies in tau-transgenic mice [67]. Activated microglia produces
interleukin-1 (IL-1), which was observed to participate in tau pathology [68]. Moreover,
activation of microglia can occur by secreted APP as well [69]. Taken together, due to their
anti-inflammatory (discussed later), ROS-scavenging and APP lowering properties, garlic
compounds can ameliorate neuroinflammation, which in turn, can be effective in preventing
excessive phosphorylation of tau.

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4.4. Role of AGE and SAC in the Context of Neuroinflammation and Protection Against
ROS
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Sporadic AD is generally a disease of the old age. Mitochondrial DNA is damaged in aging,
which is not only associated with low ATP production but also with higher production of
ROS, including highly charged free radicals [70]. In AD, deposited A can activate
microglia and activated microglia generates ROS, which play an important role in damaging
neurons [71]. Apart from ROS, activated microglia can give rise to a number of pro-
inflammatory cytochemokines like interleukins (ILs) and TNF, leading to further neuronal
loss [72]. Because of the anti-amyloid properties, AGE and other garlic derived compounds
like SAC can be helpful in ameliorating neuroinflammation. From a therapeutic point of
view, since A deposition precedes the onset of clinical dementia and the exact timing and
sequence are unknown, lowering only A loads may not be sufficient in halting or treating
AD. In this context, ROS-scavenging property of AGE and SAC would be beneficial.
Notably, we have observed a significant protection to neuronally differentiated rat PC12
cells by AGE and SAC from ROS (H2O2)-mediated insults [12].

Mechanistically, it is suggested that garlic compounds can modulate intracellular levels of

glutathione (GSH), a key enzyme responsible for cellular protection against ROS. Upon
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interaction with ROS, GSH become converted to oxidized glutathione (GSSG) by the
enzymatic action of glutathione peroxidase [73]. The ratio of GSH to GSSG is an important
parameter to determine the redox state of the cells; an increased ratio of GSH:GSSG denotes
a reduced intracellular environment and the ratio decreases in oxidative stressed condition,
which was observed in some specific regions of postmortem AD brain [74]. AGE was
observed to increase the levels of intracellular GSH [75]. Further, in a rat model, AGE
treatment was detected to preserve the levels of glutathione peroxidase and glutathione
reductase, and the latter is involved in conversion of GSSG to GSH [76]. Similar results
were observed in SAC treatment in a cell culture-based study [77]. Further, independent
treatments of AGE and SAC to APP-Tg mice revealed a significant decrease in IL-1
immunoreactive microglia numbers compared to untreated APP-Tg mice [16].

One of the important mediators of inflammation in AD is activated NFB, which is

responsible for the production of various proinflammatory cytochemokines [2]. In steady
state, NFB stays within cytosol of the cells and stays bound to an inhibitor protein IkB
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[78]. NFB activations requires phosphorylation of IkB and once IkB is phosphorylated,
NFB translocates to the nucleus and binds with promoter regions of several pro-
inflammatory cytokines genes [79]. One of the stimulatory factors for NFB activation is A
peptide, which was observed to bind with a death receptor (75 kDa-neurotrophin receptor)
resulting in NFB activation [80]. In addition to A peptides, generated ROS from A-
microglia interaction can also stimulate NFB activation [81]. Promoter mapping of
different genes shows the presence of NFB binding sites within APP, presenilin-1 and
BACE-1 genes, indicating up-regulation of these proteins following activation of NFB [2].
In this context, prevention of NFB activation is considered as a rational strategy to
ameliorate inflammation related to AD. Curcumin, one of the potential therapeutic
candidates in AD and cancer, was shown to suppress the activation of NFB [82].

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Suppression of NFB activation was also observed by SAC in cultured cells when they were
separately treated with ROS and TNF- [8384].
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Peroxisome proliferators-activated receptors (PPAR) are a class of ligand-activated

transcription factor and plays an important role in regulation of inflammation [85]. PPAR
has three distinct subtypes , and ; out of those PPAR- is involved in adipocyte
differentiation and also a target for anti-diabetic drugs like pioglitazone [86]. It was shown
that activation of PPAR- in microglia and macrophages is involved in alleviating
inflammation by decreasing the production of pro-inflammatory cytochemokines [8788].
Further, activation of PPAR- is involved in A clearance [89]. Regarding garlic
compounds, diallyl disulfide (DADS), a component of AGE was shown to increase the
expression of PPAR- in cell culture, hence can act as an anti-inflammatory agent [9091].

Neuronal destruction and synaptic loss are the endpoints of neuroinflammation seen in AD,
and cholinergic neurons in the basal forebrain are most vulnerable by this process [92].
Hence, facilitating choline uptake by cholinergic neurons or preserving the rate limiting
enzyme for choline synthesis, choline acetyl transferase (ChAT) can be considered as a
possible intervention approach. Working with cholinergically differentiated human
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neuroblastoma (SK-N-SH) cells, we have observed significant procholinergic properties of

AGE in terms of increasing high affinity choline uptake (HACU) and ChAT activity when
the cells were co-treated with AGE and ROS (H2O2)(Ray and Lahiri, unpublished data).
Similar procholinergic effects were observed in SAC and ROS cotreated cholinergic
human SK-N-SH cells (data not shown).

5. SUMMARY
Development of novel drugs to treat AD is one of the priorities in current biomedical
research as the number of AD patients and societal costs are steadily increasing. Current
FDA-approved drugs for the treatment of AD fail to completely cure the disease. Several
new drugs had been tried in clinical trials but most of them fail to demonstrate a definite
curative or disease restrictive effects in those trials. In our view, the reasons for not
achieving desirable effects with the new drugs can be due to the fact that these drugs
primarily target a single molecular pathway such as APP processing. As we reviewed here,
clinical manifestation of AD may not solely depend on deposited A but hyper-
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phosphorylation of tau, and severe neuroinflammation can also play vital roles. Based on the
aforementioned discussions, we support the proposal of the necessity of agents with
pleiotropic properties in the treatment of AD [93]. In fact, some pleiotropic properties have
been observed in recent studies with ChEI (rivastigmine and phenserine) and memantine.
Apart from their primary mode of actions, these drugs have been reported to display APP
modulating and neuropreserving properties [9496]. Rivastigmine, which increases
acetylcholine levels by inhibiting acetylcholine esterase and butyrylcholine esterase was also
observed to increase the levels of presynaptic proteins SNAP25 and synaptophysin in rat
embryonic primary neurons [97].In this context, garlic compounds AGE and SAC can have
significant effects in lowering brain amyloid load, reducing hyperphosphorylation of tau
proteins and ameliorating neuroinflammation by modulating several interconnected
pathways, however, how much these effects really translate into clinical trials remain to be

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seem.. In any case, the overall results of such intervention would have far reaching
implications. Taken together, mechanistically, AGE and SAC can have great potential for an
effective use in the prevention and treatment of AD. Particularly, as a pure synthesizable
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chemical compound, SAC can emerge as a potential therapeutic agent in preventing and
treating neurodegenerative disorders, such as AD. In order to fully understand their efficacy,
further research is warranted in larger clinical settings.

Acknowledgments
We thank Jason Bailey and Justin Long, and grant supports from the National Institutes of Health (AG18379 and
AG18884) to DKL.

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Fig. (1).
The schematic diagram shows APP processing by secretase enzymes. APP is a
transmembrane protein consists of 695771 amino acids. The major or primary cleavage
pathway of APP is shown in the left, where it is initially cleaved by -secretase enzyme.
This enzyme cleaves APP within its A domain; hence it precludes the generation of A
peptides and termed as non-amyloidogenic pathway. The second cleavage was carried out
by -secretase. As shown in the figure, -secretase pathway produces sAPP and a small P3
fragment.
In contrast, the minor or -secretase pathway is shown at the right side of the figure.
Proteolytic cleavage of APP molecule by -secretase and subsequent cleavage by -secretase
produce sAPP and A peptides and the latter is pathognomonic for AD. Generated A can
form aggregates and deposits as neuritic plaques within the brain parenchyma.
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Fig. (2).
The schematic shows potential roles of AGE and SAC in ameliorating APP and A related
pathologies in the context of AD. AGE treatment was shown to decrease the levels of APP
in Alzheimers Tg mice (refer text), which was reflected in decreased A levels. Further,
SAC was shown to possess potential effects in disaggregating A peptides. Deposited A
can activate caspases, and particularly caspase 3 activation can take a leading role in
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neuronal loss and disrupting synaptic structures. AGE was shown to inactivate caspase 3 in
APP-Tg mice. Further, increased levels of insulin in the brain have neurotrophic as well as
A clearing function. The latter is thought to be carried out by up-regulation of insulin
degrading enzyme (IDE). AGE is a natural secretagogue of insulin and indirectly capable of
reducing brain A load. It was observed that neuronal damage by deposited A can be due to
induction of endoplasmic reticulum (ER) stress, which is attenuated by garlic compounds,
such as AGE and SAC. Further, hyperlipidemia can cause enhanced A production (see the
text), and AGE treatment can substantially reduce total cholesterol levels by inhibiting
HMGCoA- reductase, the rate limiting enzyme of cholesterol biosynthesis.

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Fig. (3).
Hyperphosphorylation of tau is one of the hallmarks of AD. Apart from reduction in A-
load, preventing excessive phosphorylation of tau is also considered to be a rational strategy
for the treatment of AD. AGE and SAC treatments to the APP-Tg mice (as described in Fig.
2) decreased the levels of hyperphosphorylated tau in the brain of treated animals versus
untreated Tg mice [16]. Mechanistically, AGE and SAC were observed to inhibit the
enzyme GSK-3, a prime enzyme responsible for the hyperphosphorylation of tau.
Deposited A can also initiate hyperphosphorylation of tau protein. In this aspect, AGE and
SACs A lowering properties would be helpful in reducing hyperphosphorylation of tau.
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Further, activated microglia can release a series of cytochemokines, which also play
important roles in hyperphosphorylation of tau. AGE and SAC treatment in APP-Tg mice
were shown to decrease activated microglia load in treated Tg mice versus untreated Tg
controls [16]. AGE and SAC treatment can also be beneficial in tauopathies by decreasing
serum cholesterol levels.

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Fig. (4).
AGE and SAC can modulate different inflammatory pathways related to the pathogenesis of
AD. Microglial activation by deposited A peptides can be abridged by their potential roles
in reducing the brain A load. Further, SAC was found to inhibit the activation of the pro-
inflammatory transcription factor NFB. The latter plays an important role in the production
of several cytochemokines. Activated NFB is also responsible in generation of A from
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APP. As mentioned in the text, apart from producing cytochemokines, activated microglia
can produce ROS, leading to widespread neuronal damage. AGE and SAC treatments were
independently shown to increase the production of glutathione (GSH), an important
molecule to neutralize ROS. AGE treatment was also shown to have PPAR- agonistic
property and the latter is believed to modulate expression of several pro-inflammatory
genes. It was postulated that cholinergic neurons are most vulnerable by inflammation
associated with AD. Notably, the increased HACU and ChAT activity, as observed by AGE
and SAC treatment, is able to preserve cholinergic neurons from ROS or cytochemokines-
mediated damage.

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