Alzheimer's Disease: A Threat To Mankind: Poorti Pandey, Mritunjai Singh, I. S. Gambhir
Alzheimer's Disease: A Threat To Mankind: Poorti Pandey, Mritunjai Singh, I. S. Gambhir
Alzheimer's Disease: A Threat To Mankind: Poorti Pandey, Mritunjai Singh, I. S. Gambhir
REVIEW
Alzheimer’s disease (AD) is neurodegenerative disorder common among elderly involving deficits in
memory and cognition. There has been a long history of research and medical practice in AD
worldwide, during which different facts came into light. During recent decades with new technologies
being integrated, progress has been made in finding new genes responsible for AD, but diagnosis and
treatment. In this review we will focus on molecular, genetic and other evidence underlying the known
AD pathology.
REVIEW
Alzheimer’s disease (AD) is neurodegenerative disorder common among elderly involving deficits in
memory and cognition. There has been a long history of research and medical practice in AD
worldwide, during which different facts came into light. During recent decades with new technologies
being integrated, progress has been made in finding new genes responsible for AD, but diagnosis and
treatment. In this review we will focus on molecular, genetic and other evidence underlying the known
AD pathology.
Dementia is a serious loss of cognitive ability, is et al, 2003). The risk of AD rises exponentially with
far more common in the geriatric population, it may age, such that up to 47% of individuals over the age
occur before the age of 65 (Fadil et al, 2009). of 80 develop AD. More women than men have
Dementia is not merely a problem of memory. It Alzheimer’s disease and other dementias. Almost
reduces the ability to learn, reason, retain or recall two-thirds of all Americans living with Alzheimer’s
past experience and there is also loss of patterns of are women. (Plassman et al, 2007) Based on
thoughts, feelings and activities. It is caused by estimates from ADAMS, 16 percent of women aged
various diseases that result in damaged brain cells, 71 and older have Alzheimer’s disease or other
or connections between brain cells as listed in table dementia compared with 11 percent of men.
1. For diagnosing dementia, Diagnostic and (Seshadri et al, 1997) According to report on AD
Statistical Manual of Mental Disorders, Fourth between 2000-2008 deaths due to AD increased
Edition (DSM-IV) is preferred. (American 66% while previously reported number one cause of
Psychiatric Association, 1994) death, heart disease decreased 13 %. Based on the
• Early-onset Alzheimer's: This is a rare form inherited. In affected families, members of at least
(less than 10% cases) of AD in which people are two generations have had AD. FAD is extremely
diagnosed before age of 65. (Alzheimer’s rare, accounting for less than 1% of all cases of AD.
Association, 2006) It has a much earlier onset (often in the 40s) (Scott
common form of AD, accounting for about 90% of On average, AD patients live about 8 years after
cases and usually occurring after age 65. Late-onset initial diagnosis, although the disease can last for as
Alzheimer's disease strikes almost half of all people long as 20 years. The areas of the brain that control
over the age of 85 and may or may not be memory and thinking skills are affected first but, as
hereditary. Late-onset dementia is also called the disease progresses, neurons in other regions of
sporadic AD. (Scott et al, 2008) the brain are also affected. Eventually, the patient
with AD will need complete care, adding further
• Familial Alzheimer's disease (FAD): This
emotional, physical, and financial costs to the family
is a form of AD that is known to be entirely
(Vitaliano et al, 2003).
Flowdiagram 1 The sequence of pathogenic events leading to AD proposed by the amyloid cascade
hypothesis. The curved arrow indicates that Aβ oligomers may directly injure the synapses
and neurites of brain neurons, in addition to activating microglia and astrocytes. (Adopted
from Hardy, et al,2002 )
Neurofibrillary tangles and senile plaques are the involves a series of brain scans, cognitive
two characteristic hallmarks of disease, observed in assessment and laboratory tests as mentioned in
alzheimer’s brain (Scott et al, 2008; Tiraboschi et al, table 2. These help identify physical and cognitive
2004). Both amyloid plaques and neurofibrillary changes associated with Alzheimer’s disease, and
tangles can be visalised by microscopy in brains of rule out other conditions, causing similar symptoms.
those afflicted by AD. Plaques are dense, mostly
Molecular and Genetic aspect of AD
insoluble deposits of amyloid-beta peptide and
Amyloid precursor protein (APP) and Neuritic
cellular material (dystrophic axons & dendrites)
Plaques
primarily. Activated microglia & reactive astrocytes
outside and around neurons as well as α-synuclein, APP is an integral membrane protein as shown
ubiquitin, apolipoprotein E, presenilins and alpha in figure 1, expressed in many tissues and
antichymotrypsin,are also observed (Yankner, 1991; concentrated in the synapses of neurons. In humans,
Hardy, 1991; Joachim, 1992 Selkoe, 1994; Dewji, the gene for APP is located on chromosome 21
1996; Wang, 1991; Kudo, 1994). A recent study has (Table 3) and contains at least 18 exons in 240
shown that Lewy bodies are present in the brains of kilobases (Thomas et al, 2007) Several alternative
about 60% of AD cases (Hamilton, 2000). Tangles splicing isoforms of APP have been observed in
(neurofibrillary tangles) are aggregates of the humans, ranging in length from 695 to 770 amino
microtubule-associated protein tau which has acids with certain isoforms preferentially expressed
become hyperphosphorylated and accumulate inside in neurons; Mutations in this gene cause excessive
the cells themselves. Although many older cleavage by the β- and γ-secretase enzymes, instead
individuals develop some plaques and tangles as a of normal cleavage by the α-secretase enzyme
consequence of aging, the brains of AD patients (shown in flowdiagram 2). The result is increased
have a greater number of them in specific brain production of toxic β-amyloid fragments a 39- to 42-
regions such as the temporal lobe. amino acid peptide, which are converted into
insoluble aggregates that form senile plaques in
Diagnosis
brain tissue associated with Alzheimer's disease
Diagnosis of AD is not a single step process &
Flowdiagram 2: Cascade of APP cleavage in normal (left) and diseased state (right)
chromosome 14 (Shellenberg et al, 1992; Hardy marker of neuronal damage was detectable in
2001), and presenilin-2, located on chromosome 1 cerebrospinal fluid (CSF). Elevated levels of CSF t-
(Nishimura et al, 1999) (Table 3). Presenilins are a tau have been observed in patients with AD, even in
family of related multi-pass transmembrane proteins those with mild dementia, compared with healthy
that function as a part of the gamma-secretase elderly controls. However, CSF t-tau levels are of
intramembrane protease complex and mutations lead limited value in the differential diagnosis of AD,
to excessive cleavage by the γ- secretase enzyme. because they can be increased in other dementia
Aβ 42 is more likely to aggregate to form plaques in disorders. Therefore, it appears likely that t-tau
the brain than Aβ 40. Presenilin mutations lead to an levels reflect neuronal degeneration rather than AD-
Aβ 40, although the total quantity of Aβ produced phosphorylated tau (p-tau) protein in the CSF
Tau protein located on chromosome 17 (Table The protein, ApoE, is mapped to chromosome
3), are known to stabilize microtubules. They are 19, (Table 3) and is known play fundamental role in
abundant in neurons in the central nervous system maintenance and repair of neurons (Mahley, 1998;
and are less common elsewhere. Six tau isoforms Mahley et al, 2000). The APOE gene consists of
exist in brain tissue, and they are distinguished by four exons and three introns, totaling 3597 base
their number of binding domains. Three isoforms pairs. ApoE is polymorphic with three major
have three binding domains and the other three have isoforms, ApoE2 (5-10%), ApoE3 (60-70%), ApoE4
four binding domains. The binding domains are (15-20%), which translate into three alleles of the
located in the carboxy-terminus of the protein and gene: Higher frequency of the ApoE4 allele is found
are positively-charged (allowing it to bind to the in patients with AD than in the general population
negatively-charged microtubule). The isoforms with (Corder et al, 1993). However, the pathogenetic
four binding domains are better at stabilizing mechanism of ApoE4 in AD is unknown, there are
microtubules than those with three binding domains. few proposed mode of action . ApoE4 is known to
The isoforms are a result of alternative splicing in inhibit neurite outgrowth, (Nathan et al, 1994;
exons 2, 3, and 10 of the tau gene. Bellosta et al, 1995) disrupt neuronal cytoskeleton
(Nathan et al, 1994; Bellosta et al, 1995; Holtzman
Hyperphosphorylation of the tau protein (tau
et al, 1995), stimulate tau phosphorylation (Tesseur
inclusions, p-Tau) can result in the self-assembly of
et al, 2000; Huang et al, 2001) & causes
tangles of paired helical filaments and straight
neurodegeneration (Buttini et al, 1999). In vitro
filaments, which are involved in the pathogenesis of
studies have shown that ApoE3 binds to the
AD and other tauopathies (Kosik, 1994). Abnormal
microtubule associated protein tau with high avidity,
hyperphosphorylation of the microtubule- associated
whereas ApoE4 does not bind tau, suggesting that
tau protein and its incorporation into neurofibrillary
ApoE3, but not ApoE4, by binding to tau, slows the 4. ADAM 10 present on chromosome 15
degree of tau phosphorylation and self assembly into (15q22.1) is an α- secretase, cleaves APP in a way
paired helical filaments (Strittmatter al, 1994). It has leading to P3 formation thus ceases the Aβ peptide
also been suggested that intraneuronal ApoE, by formation by β- secretase (Kim et al, 2009).
interaction with tau protein, may influence the These 4 genes mentioned above are responsible
neuronal pathology in AD, from early in the disease for late onset of AD; mutation in any of them will
(Han et al, 1994). increase the risk of AD.
These allelic forms differ from each other only
Other Risk Factors
by amino acid substitutions at positions 112 and
In addition to aging & genetic factor there are
158. E3 has Cys-112 and Arg-158 whereas E2 has
many other risk factors like head injury (traumatic
Cys at both positions and E4 has Arg (Mahley et al,
brain injury) (Lye et al, 2000), strokes &
1999). People who inherit one or two APOE ε4
ministrokes, unhealthy habits (Anstey et al, 2007),
alleles tend to develop AD at an earlier age than
high cholesterol (Sjogren et al, 2005), low level of
those who do not have any. APOE ε4 is called a
formal education & low social-economic status.
risk-factor allele because it increases a person’s risk
Cardiovascular and cerebrovascular and vascular
of developing AD with exceptions.
risk factors (Korf et al, 2005; Decarli, 2004)
Besides these genes with technological
cardiovascular disease and subgroups of patients
advancement in genetic analysis over last few years
with peripherial arterial disease (Newman et al,
lead to the discovery of new genes associated with
2005) and elevated plasma total homocysteine
late onset of AD. With the help of genome wide
concentrations and low serum folate concentrations
association study (GWAS) it is easy to screen
(Ravaglia et al, 2005). Zinc metabolism
several genes at a time which led to the discovery of
(Mocchegiani et al, 2005), loss of microglial cell
novel genes, few among them are
function (Streit, 2005); and decreased melatonin
1. CLU gene present on chromosome 8
(Srinivasan et al, 2005). Environmental factors, such
(8p21), which is another apolipoprotein , like Apo
as heavy metal exposure (Treiber, 2005), have been
E, may play a role in clearing β- amyloid out of
investigated for many years.
brain (Harold et al, 2009).
Nutrition and lifestyle factors, such as midlife
2. PICALM (phosphatidyl inositol binding
obesity (Kivipelto et al, 2005), lack of exercise
clathrin assembly protein), present on chromosome (Kiraly et al, 2005) and watching too much
11 (11q14) which seems to be involved in recycling television in middle-adulthood (Lindstrom et al,
of cell membrane protein at synapses (Harold et al, 2005), have been associated with an increased risk
2009). for AD. Even a man’s height has been associated
3. CR1 (complement receptor 1) present on with risk. Researchers have reported that short men
chromosome 1 (1q32) is an immunoprotein, are at increased risk (presumably due to its
responsible for inflammatory response may be association with childhood nutrition and other risk
involved in clearing β- amyloid from brain ( Jun et factors) for dementia (Beeri et al, 2005).
al, 2010). Down’s syndrome results in trisomy of
chromosome 21. Those suffering from this disease
& survive beyond 40s are at high risk of developing higher than body can get rid of them thus leading to
abnormal brain changes that characterize AD but not toxic effect on every cell in body, leading to aging &
all of them develop dementia (Lott et al, 2005; several brain pathologies.
Nistor et al, 2007), this led to the discovery of the Oxidative and Nitrosylative Damage Hypothesis
APP gene on chromosome 21 (Goldgaber et al, states that, reactive oxygen species (ROS) and
1987). People with Down syndrome are particularly reactive nitrogen species (RNS) are important in the
at risk for a form of early onset Alzheimer's disease initiation and promotion of neurodegeneration in the
(Alzheimer’s Association, 2006). brains of patients with AD (Anderton B). Some of
Diabetes mellitus (DM) and AD are the two these free radicals are released during inflammatory
most devastating health problems in elderly. reactions, whereas others are formed during normal
Diabetes is associated with cognitive decline and oxidative metabolism and auto-oxidation of certain
dementia. Indeed, individuals with diabetes are neurotransmitters and by β-amyloid. Thus, the role
nearly 1.5 times more likely to experience cognitive of free radicals in the pathogenesis of AD should be
decline and frank dementia than individuals without considered, at least in part, independent of
diabetes (Cukierman et al, 2005). Multiple possible inflammatory reactions. Clinical studies showing the
mechanisms for this association have been beneficial effects of high dose antioxidants such as
proposed, including direct effects of hyperglycemia, vitamin E (Sano et al, 1997) and NADH
insulin resistance, and insulin- induced amyloid-β (Birkmayer, 1996) in the treatment of AD support
peptide (Aβ) amyloidosis in the brain as well as the role of free radicals in progressive degeneration
indirect ischemic effects of DM-promoted of neurons.
cerebrovascular disease (Biessels et al, 2005).
Treatment
Diabetes increases the risk of Alzheimer disease and
There are currently no means for reversing the
vascular dementia. The risk is stronger when
pathological processes of AD. Normal physiology of
diabetes occurs at mid-life than in late life (Xu et al,
brain deals in transmitting messages (impulses)
2009).
along nerve fibre by electrical mechanism. This
Oxidative stress
electricity is insufficient to cross junction, thus
The search for risk factors is diverse and impulse release neurotransmitter acetylcholine
ongoing, and includes a variety of cellular processes (ACh) which diffuses across junction to stimulate
such as oxidative stress, disturbed protein next cell, after purpose is solved these are eliminated
metabolism, and their interaction (Calabrese et al, by cholinesterase, otherwise disastrous stimulating
2003). Oxidative stress is believed to be a critical downstream cell. In diseased state, as nerve endings
factor in normal aging (Sohal et al, 1996) and become sick so the concentration of ACh released
neurodegenerative diseases such as Parkinson’s get progressively smaller, hence unable to transmit
disease and amyotrophic lateral sclerosis. Oxidative message across junction Thus cholinesterase
stress is a threatening situation when oxidants inhibitors are used to prevent cholinesterase from
overwhelm antioxidants defenses, or when small destructing ACh. Few drugs in this category are
molecules like reactive oxygen species (ROS) & Galantamine, Rivastigamine and Donepezil (Doody
reactive nitrogen species (RNS) accumulate at a rate et al, 2001)
researchers worldwide. The prevalence of this S., Schmeidler, J., Goldbourt, U. (2005)
disease is predicted to increase 3-fold over the next Relationship between body height and
30 years and to date no reliable and conclusive dementia. Am J Geriatr Psychiatry; 13:
presymptomatically of susceptibility risk. Purpose of Bellosta, S., Nathan, B.P., Orth, M., Dong, L.M.,
this review is to highlight the facts related to AD, so Mahley, R.W. Pitas, R.E. (1995) Stable
as to aid the development of new strategies for expression and secretion of apolipoproteins
diagnosis and treatment. E3 and E4 in mouse neuroblastoma cells
produces differential effects on neurite
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