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The Open Neurology Journal, 2015, 9, 9-14
9
Open Access
Homocysteine Induced Cerebrovascular
Alzheimer’s Disease Etiology
Dysfunction:
A
Link
to
P.K. Kamat, J.C. Vacek, A. Kalani and N. Tyagi *
Department of Physiology and Biophysics, School of Medicine, University of Louisville, and Louisville, KY 40202, USA
Abstract: A high serum level of homocysteine, known as hyperhomocystenemia (HHcy) is associated with vascular
dysfunction such as altered angiogenesis and increased membrane permeability. Epidemiological studies have found
associations between HHcy and Alzheimer’s disease (AD) progression that eventually leads to vascular dementia (VaD).
VaD is the second most common cause of dementia in people older than 65, the first being AD. VaD affects the quality of
life for those suffering by drastically decreasing their cognitive function. VaD, a cerebrovascular disease, generally occurs
due to cerebral ischemic events from either decreased perfusion or hemorrhagic lesions. HHcy is associated with the
hallmarks of dementia such as tau phosphorylation, A aggregation, neurofibrillary tangle (NFT) formation,
neuroinflammation, and neurodegeneration. Previous reports also suggest HHcy may promote AD like pathology by more
than one mechanism, including cerebral microangiopathy, endothelial dysfunction, oxidative stress, neurotoxicity and
apoptosis. Despite the corelations presented above, the question still exists – does homocysteine have a causal connection
to AD? In this review, we highlight the role of HHcy in relation to AD by discussing its neurovascular effects and
amelioration with dietary supplements. Moreover, we consider the studies using animal models to unravel the connection
of Hcy to AD.
Keywords: Alzheimer’s disease, blood brain barrier, cerebrovascular pathology, homocysteine, vascular dementia,
INTRODUCTION
METABOLISM OF HOMOCYSTEINE
Homocysteine (Hcy), a key metabolic intermediate in
sulfur-containing amino acid metabolism [1] is an
independent risk factor for cerebrovascular disease [2]. Hcy
is an excitatory amino acid, which markedly enhances the
vulnerability of neurons to oxidative injury [3]. An elevated
plasma level of Hcy (>14 μM) is termed as hyperhomocysteinemia (HHcy), which has emerged as an independent risk
factor for several neurodegenerative diseases such as
Alzheimer’s disease (AD) [4], stroke [5] and vascular
dementia [6]. In recent years, it has become clear that
elevated levels of Hcy elicits neuronal death in a variety of
neuronal cell types, including hippocampal and cortical
neurons [7], cerebellar granule cells [8], and SH-SY5Y cells
[9]. One study has shown an association with Hcy and
hippocampal plasticity and synaptic transmission resulting in
learning and memory deficits [10]. Recently, it has been
suggested that intracerebral administration of Hcy affected
both long- and short-term memory [3]. One explanation for
the mechanism of Hcy induced neurotoxicity is the autooxidation of Hcy leading to cellular oxidative stress through
the formation of reactive oxygen species, which causes
neuroinflammation and apoptosis [11].
Methylenetetrahydrofolate reductase (MTHFR), a key
enzyme in the metabolism of folate and homocysteine,
catalyzes the synthesis of the main circulatory form of folate,
5-methyltetrahydrofolate (5-methylTHF). 5-MethylTHF is
used for remethylation of homocysteine to methionine and Sadenosyl methionine (SAM), a universal methyl donor [12].
In the liver and kidneys, the choline metabolite betaine can
serve as an alternate methyl donor for homocysteine
remethylation, particularly when folate-dependent remethylation is disturbed [13]. Homocystinuria, an inborn error
of metabolism, can be caused by different genetic
deficiencies, including severe MTHFR deficiency. MTHFR
mutations in homocystinuric patients are associated with low
levels of enzyme activity (0–20%), marked HHcy and
decreased levels of serum folic acid, methionine and SAM
[14]. Clinical features vary but often include developmental
delays, mental retardation, motor abnormalities, psychiatric
disorders, cerebral atrophy, demyelination, and thrombosis
[15]. Several studies observed high plasma Hcy in patients
with mild cognitive impairment, AD, depression and
schizophrenia suggesting the association between HHcy and
association with HHcy and neurological pathology [16].
*Address correspondence to this author at the Department of Physiology
and Biophysics, Health Sciences Center, A-1201, University of Louisville,
Louisville, KY 40202; Tel: 502-852-4145; Fax: 502-852-6239;
E-mail: n0tyag01@louisville.edu
1874-205X/15
HHcy has been associated with B vitamin deficiencies of
folate, B6, and B12 due to their role as cofactors in the
metabolism of Hcy. Vitamin B12 is also a cofactor in other
methylation reactions. In particular, vitamin B12 deficiency
has been shown to result in cognitive impairment [17]. It is
not clear whether the cognitive impairment is a direct
consequence of B12 deficiency or whether it is a result of the
2015 Bentham Open
10 The Open Neurology Journal, 2015, Volume 9
Kamat et al.
Fig. (1). Homocysteine-Folate Pathway: The metabolic interactions between folate, methionine and homocysteine are shown here. Folate
from the diet is absorbed and converted to methylenetetrahydrofolate (MTHF) with the formation of high-energy phosphate bonds by the
action of MTHF reductase (MTHFR), methyl tetrahydrofolate is yielded which methylates homocysteine to methionine. Methionine is
converted to SAM, the universal methyl donor. SAM provides methyl groups for several nucleic acid methylation reactions and gets reduced
to S-adenosylhomocysteine which then reforms homocysteine and reinitiates the cycle. Abbreviations: SAM; S-adenosylmethionine, SAH;
S-adenosylhomocysteine, MTHFR; methylenetetrahydrofolate reductase; B6 and B12; Vitamin B6 and Vitamin 12 respectively.
subsequent HHcy. One such mechanism for this observation
could be linked to myelin basic protein. Myelin basic protein
is methylated on an arginine group and a defect in
methylation could produce an unstable protein, leading to
neurological disorders [18].
As mentioned above folic acid is a B-group water-soluble
vitamin. It is comprised of the aromatic pterydine ring linked
to para-aminobenzoic acid and one or more glutamate
residues. Folate derivatives are important vitamins that
transfer one-carbon units for several critical cellular
reactions. The in folate cycle in association with Hcy is
depicted in Fig. (1). Neuronal function relies heavily on the
supply of methyl groups for such functions as
neurotransmitter synthesis and membrane lipid metabolism.
Furthermore, folates are required for the metabolism of Hcy.
The regulation of Hcy allows for the maintenance of
neuroplasticity and neuronal integrity, when HHcy develops
neurotoxicity is known to occur [19]. Such detrimental
effects can be attributed to mechanisms such as
excitotoxicity and mitochondrial dysfunction, which may
lead to apoptosis [20]. One study has shown HHcy in mice
along with B-vitamin deficiency diet cause cerebral
microvascular rarefaction which may bring about cognitive
dysfunction. Clinical reports suggest that disease progression
of a dementia patient with HHcy and associated morbidities
can be lowered by supplementation of food or nutrient
enriched with B vitamins. Another study has shown the food
supplementation of folates and vitamin B12 ameliorating
HHcy and thus Hcy induced tau hyperphos-phorylation as
well as protein phosphatase-2A (PP2A) inactivation [21].
After reviewing the literature it is apparent that the
association with HHcy and cognitive impairment is evident
and should be elucidated further.
OXIDATIVE STRESS AND NEUROINFLAMMATION
Experimental and clinical studies have shown numerous
inflammatory mediators being implicated in neurological
disorders. Histological analysis of human brain tissue from
individuals with AD strongly suggests the existence of a
chronic inflammatory state in brain tissue leading to
neuronal loss [22]. Other studies confirm the association of
oxidative stress, HHcy, altered cerebrovascular remodeling
and neuroinflammation with AD [3, 23]. HHcy has been
documented to show changes in the structure and function of
cerebral blood vessels via oxidative stress, which plays a key
role in cerebrovascular endothelial dysfunction [24].
Oxidative stress and endothelial dysfunction led to structural
deformities in the cerebral blood vessels that can impair
perfusion with subsequent neuronal dysfunction and
recognized as an important contributing factor in the
pathogenesis of AD and VaD. One novel study has shown
intracerebroventricular injections of Hcy in rats inducing
lipid peroxidation, increased malondialdehyde and
superoxide anion levels in brain tissue leading to impaired
memory retention in the passive avoidance learning test [25].
It is apparent that Hcy injections in rodent brains led to
severe oxidative stress, neuroinflammation and cognitive
impairment [3, 10].
MMPS AND
DAMAGE
BLOOD
BRAIN
BARRIER
(BBB)
HHcy causes increased expression of matrix
metalloproteinases (MMPs) [26]. Oxidative stress has been
suggested to be involved in neurovascular dysfunction in
part by activation of MMPs along with apoptosis induced by
Homocysteine Induced Cerebrovascular Dysfunction
Hcy [3]. One study analyzing this effect used a heterozygous
cystathionine-b-synthase knockout mouse model; the
resulting HHcy showed increased brain permeability in
relation to increased MMP-9 and MMP-2 activity and
suppression of tissue inhibitors of metalloproteinase (TIMPs)
[27]. These effects led to the degradation of extracellular
matrix (ECM) and disruption of the BBB. In mild HHcy,
increased permeability of the BBB precedes the onset of
cerebral pathology related to the progression of AD [28].
MMPs are membrane-bound, zinc-binding proteolytic
enzymes and activated by other proteases and free radicals in
the ECM. The MMPs are essential for the breakdown of
ECM components of cerebral blood vessels and neurons
[29]. In general, MMPs are released as a zymogen and
activated by proteolytic cleavage of the N-terminal domain.
MMP-9 is usually low and its expression can be induced by
various pro-inflammatory factors such as cytokines. MMP-2
is constitutively expressed in several cell types and rarely
inducible. In the central nervous system (CNS) MMPs,
especially MMP-9, are implicated in the pathogenesis of
several CNS diseases such as stroke, AD and multiple
sclerosis [30]. Several pro-inflammatory factors including
cytokines, endotoxins, and oxidative stress have been shown
to up-regulate MMP-9 in astrocytes in vitro [31]. The
accumulation of toxic free radicals plays an essential role in
BBB disruption through MMP activation [32]. MMPs, in
particular MMP-2 and MMP-9, are heavily implicated in the
pathogenesis of hemorrhagic events; leaky vessels and BBB
damage [33]. These events escalate to clinically significant
neurologic disease.
ENDOTHELIAL DYSFUNCTION
Endothelial cells are key modulators of inflammation and
angiogenesis [34]. Several studies confirm endothelial
dysfunction may be partly caused by oxidation related to the
effects of raised total plasma homocysteine [35]. Endothelial
dysfunction is also increasingly implicated in the
development of neurodegenerative diseases such as AD [36].
Cell adhesion molecules play an important role in
inflammatory responses in brain endothelial cells. The
vascular cell adhesion molecule (VCAM-1) and intercellular
adhesion molecule 1 (ICAM-1), one of the inducible
immunoglobulins expressed on several cell types, play an
important role in a number of inflammatory and immune
responses [37]. Upregulation of these adhesion molecules in
astrocytes is required for monocyte-astrocyte interaction,
leading to an increased infiltration of circulating monocytes
into the CNS observed in patients with AD. Endothelial cells
in the brain regulate the neuronal milieu both by their
synthetic functions as well as by their BBB regulation.
However, chronic inflammation through circulating
monocytes and cytokines are tightly linked to diseases
associated with endothelial dysfunction. Therefore,
disturbances in endothelial function could result in a noxious
neuronal environment facilitating AD pathogenesis.
BBB DYSFUNCTION AND AD PATHOLOGY
The BBB is formed by highly specialized endothelial
cells that line brain capillaries and allow specific molecular
The Open Neurology Journal, 2015, Volume 9
11
exchange between micro-vessels, microglia and neurons.
The BBB relies on the tight junctions present between
endothelial cells of the capillaries to provide a relatively
closed environment for the brain. Alteration of tight junction
proteins promotes BBB dysfunction, which is associated
with a reduction of cerebral blood flow, hypoxia and
accumulation of neurotoxic molecules such as free radicals
and inflammatory molecules in the brain [38]. In contrast to
leaky vessels in visceral organs, the BBB restricts entry of
polar molecules into the brain but at the same time allows
limited nutrients such as vitamins, glucose, and amino acids
through specific transporters [39]. BBB disruption promotes
micro-vascular degeneration, accumulation of toxic
substances (Beta amyloid, NFT and Tau hyperphosphorylation), neurodegeneration, neuroinflammation and
memory impairment [40].
HOMOCYSTEINE AND VASCULAR DEMENTIA
Vascular dementia (VaD) is defined as the loss of
cognitive function resulting from cerebrovascular disease
that damages the hippocampus and other cognitive centers,
which important for memory, cognition, and behavior [41].
It is the second most common form of dementia after AD,
accounting for 20% of all dementia cases worldwide [42]. In
addition, VaD is thought to occur in 20% to 55% of AD
cases [43]. Previous studies, which have induced HHcy in
rodents, produced cognitive decline, systemic vascular
inflammation, atherosclerosis and a loss of central
cholinergic neurons [44]. AD and VaD share many risk
factors, one such being HHcy, thus suggesting related
etiology and pathogenesis [45]. It is common for patients of
each disease to share similar symptoms [46]. Therefore, the
differentiation from AD to VaD is based on evidence of
cerebrovascular function alteration and pathology in VaD
(Fig. 2). Furthermore, it has been suggested that dementia
prevention can be effective without delay if the vascular
components are aggressively targeted through the treatment
of vascular risk factors such as HHcy [47].
HOMOCYSTEINE AND ALZHEIMER’S DISEASE
Alzheimer's disease (AD) is characterized by
cerebrovascular damage and neuronal atrophy leading to a
progressive cognitive decline which is also known as VaD
[48, 49]. AD shares many risk factors with cerebrovascular
diseases, thus hinting at a potential vascular etiology [50,
51]. In addition, numerous epidemiological studies have
observed micromolar increases in Hcy to be associated with
increased risk of stroke, white matter disease, and cognitive
dysfunctions that range in severity from mild cognitive
impairment to AD [52]. The hallmark histologic findings for
AD include beta-amyloid (A) plaques and angiopathy,
NFTs containing hyperphosphorylated tau proteins [53],
BBB leakage, and increased microglial reactivity [23]. One
hypothesis suggests the accumulation of A is the most
important cascade for the development of AD. A-peptides
(40, 42 or 43 amino acids) originate from the amyloid
precursor protein (APP) by cleavage with -, - and secretases during sudden A-production. Clearance of the
peptides may trigger neurodegeneration [54]. In AD
12 The Open Neurology Journal, 2015, Volume 9
Kamat et al.
Fig. (2). Homocysteine and Vascular Dementia: Flow diagram showing the mechanism of homocysteine induced vascular dementia.
Homocysteine produces oxidative stress in the initial stage. Further oxidative stress leads to activation of MMPs as well as PP2A inhibition.
Activated MMPs promote matrix degradation, vascular inflammation, endothelial dysfunction and finally BBB dysfunction. Activated
MMPs may also promote beta amyloid (A) cleavage and neuroinflammation. PP2A inhibition by homocysteine causes Tau
hyperphosphorylation. These events result in the neurofibrillary and senile plaque formation in the brain. Further, senile plaque and
neurofibrillary tangle formation promotes neurodegeneration and thus initiates AD and vascular dementia like symptoms.
progression Hcy over long periods may cause dysfunctional
A-clearance as well as BBB impairment which may initiate
cerebrovascular dysfunction or inflammatory processes
leading to the development of AD [46].
BETA AMYLOID (A) AND TAU HYPERPHOSPHORYLATION
A plaques and Tau hyperphosphorylation are
characteristic features of AD associated with the deterioration of cognitive functions [55]. Neurofibrillary tangles,
senile plaques, and synaptic loss in the affected brain regions
such as cortex and hippocampus are other typical features of
AD [56]. A potential mechanistic association of these
features could be traced to HHcy. One study concluded
HHcy increases levels of A transporters in micro-vessels
that form the BBB, elevates A content (A40 and A42),
and impairs cognitive function [57]. Chai et al. [58]
demonstrated the elevation of plasma Hcy could induce A
peptide accumulation and increase AD-like tau hyperphos-
phorylation in rats [59]. In addition to this Hcy sensitizes the
neurons to A toxicity and impairs DNA repair in
hippocampal neurons [60]. Another study with folate and
vitamin-B12 treatment in rodents showed decrease A
production and attenuation of memory impairment induced
by HHcy [58] Furthermore, Zhang et al. [59] reported
homocysteine injections in intracerebroventricular regions
rat brain which dispersed into whole brain led to increased
levels of amyloid precursor protein (APP) levels. The
associations of HHcy on AD features in animal models with
a normal gene background are not currently elucidated and
make for a novel ground of research. New efforts using these
models could give clues not only to AD but also VaD and
other dementia subtypes.
ANIMAL MODEL OF HHCY SHOW POTENTIAL
LINK TO AD
Several animal models have shown a role of HHcy in
cerebrovascular pathology, cognitive decline and learning
disabilities [44]. Koladiya et al. [61] reported that HHcy
Homocysteine Induced Cerebrovascular Dysfunction
induced via administration of L-methionine in rodents has
been reported to produce a significant degree of VaD. Other
studies have shown intracerebral Hcy injections in rodent
brains to produce AD like symptoms [3, 10]. Another project
has shown a transgenic mouse model such as CBS
(Cystathione- synthase) knockout mice inducing HHcy
leading to A toxicity [62]. It is important to note that a
reported linking of Hcy to A induced hippocampal
neurotoxicity has been observed, a potential source of AD
[60].
The Open Neurology Journal, 2015, Volume 9
ACKNOWLEDGEMENTS
This work is supported in part by the NIH grant
HL107640 to NT.
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CONCLUSION
Although AD and many other dementia subtypes are not
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reiterate many of the subtypes share common risk factors
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ABBREVIATIONS
Hcy
=
homocysteine,
HHcy
=
hyperhomocysteinemia,
AD
=
Alzheimer’s disease,
VaD
=
vascular dementia,
A
=
Beta amyloid,
ROS
=
reactive oxygen species,
BBB
=
blood brain barrier,
MMPs
=
matrix metalloproteinases,
MTHFR
=
methylenetetrahydrofolate reductase,
SAM
=
S-adenosylmethionine,
(TIMPs)
=
tissue inhibitor of metalloproteinases
[16]
(ECM)
=
extracellular matrix
[17]
(CNS)
=
central nervous system
[11]
[12]
[13]
[14]
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[18]
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
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Revised: December 01, 2014
Accepted: December 11, 2014
© Kamat et al.; Licensee Bentham Open.
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