Alzheimer¡¯s Disease: Recent Advances
Ritu
Arora, Anshika Mittal, Rita Kakkar
Ritu Arora, Anshika
Mittal, Rita Kakkar, Computational
Chemistry Group, Department of Chemistry, University of Delhi, Delhi-110 007,
India
Correspondence to: Rita Kakkar, Computational Chemistry Group,
Department of Chemistry, University of Delhi, Delhi-110 007, India
Email: rkakkar@chemistry.du.ac.in
Telephone:
+91-1127666313
Fax:
+91-27666605
Received: June 5, 2015
Revised: August 8, 2015
Accepted: August 12, 2015
Published online: September 22, 2015
ABSTRACT
These days our
society is combating against a neurodegenerative disease called Alzheimer¡¯s
disease which is an age-related dementia. The concern has become graver as the
disease may not be a necessary outcome in the oldest old and may even thrive in
an age of thirties or forties. Alzheimer¡¯s impairs a person¡¯s cognitive ability
and gradually leads to loss of bodily functions, making them dependent on
others. Plaques and tangles are the two prime hallmarks in the disease
progression. Their escalation in the cortex gradually causes shriveling up of
the brain. Unfortunately, the neurodegenerative changes are irreversible and no
treatment can retard the progression of the disease. New therapeutic
interventions related to Alzheimer¡¯s disease are needed to be explored in order
to apprehend the order of its occurrence and retard its progression.
Key words: Dementia; AD; Neurodegeneration; Progression; Clinical
symptoms; Protein aggregation; Apoptosis; Amyloid plaques; Neuroinflammation;
Preventions; Biomarkers
Arora R, Mittal A,
Kakkar R. Alzheimer¡¯s Disease: Recent Advances. Journal of
Biochemistry and Molecular Biology Research 2015; 1(3): 87-104 Available from:
URL: http://www.ghrnet.org/index.php/jbmbr/article/view/1240
INTRODUCTION
Alzheimer¡¯s disease (AD)[1,2,3] is one of the most recurrent
types of dementia which accounts for around 60-80 % of the cases of dementia[4].
¡°Dementia¡± is a blanket term used to describe any brain disease that impairs a
person¡¯s cognitive ability i.e. memory, behaviour and ability to think clearly[5].
The other forms of dementia include Parkinson¡¯s disease[6],
Huntington¡¯s disease[7], Lewy body dementia[8], vascular
dementia[9], Creutzfeldt-Jakob disease[10],
frontotemporal dementia, progressive supranuclear palsy[11,12] and
normal pressure hydrocephalus[13].
The different
forms of dementia run counter in terms of the distinct pattern of symptoms and
abnormalities in the brain. Alzheimer¡¯s Association published the definitions
of the various forms of dementia, suggesting overlapping features in them[14,15].
Dementia is neurodegenerative in nature and the associated conditions develop
due to malfunctioning or death of nerve cells (called neurons) in the brain
which may become more common with age. In AD, which is an age-related dementia,
the neurodegenerative changes in brain gradually cause loss of basic bodily
functions like speaking, walking and swallowing and, ultimately, prove to be
fatal. It is a progressive ailment i.e. the degeneration in the structure and
chemistry of the brain increases over time.
Cognitive
aging and AD were explored in a review[16]. It was suggested that
the latter is critical to genetics and previous brain injuries and, although
more prevalent in the aging population, it is not a necessary outcome only in
the oldest old. Some believe environmental and intergenerative approaches can
better incorporate ¡°existent world¡± ecological and psychosocial models of
health to recalibrate the study of the disease[17]. Additionally,
factors like education[18], diet, exercise and cognitive stimulation
all seem to make Alzheimer¡¯s more likely.
AD was first
identified more than 100 years ago by a German psychiatrist and
neuropathologist Alois Alzheimer and was named after him[19,20,21].
Despite its long history, the research into its characteristics,
pathophysiology, diagnosis, prevention, risk factors, management and treatment
has gained impetus only in the last few years. In spite of the wealth of
research that has been reported during these years, the changes in the brain
that stimulate the development of Alzheimer¡¯s and their order of occurrence
largely remain a moot question. Therefore, this work is dedicated to review AD,
the most common dementia in aging population, and to compile the recent
advances in its ongoing research.
Onset of
Alzheimer¡¯s disease
The categorization of AD is generally based on the differences in age of
its onset and can be broadly classified as early-onset and late-onset AD. It
can also be categorized as familial and sporadic AD on the basis of differences
in the genetic cause[22]. Neurologists generally have a belief that
both have similar overall sequence of symptoms and increasing impairments.
Early-onset alzheimer's
Less than 10% of all AD subjects are pinpointed with the disease before
age 65; this is referred to as early-onset alzheimer¡¯s. This is an
uncommon form of AD, known to develop in a person¡¯s 30¡¯s, 40¡¯s, and 50¡¯s (and
very scarcely in the late 20¡¯s). Ironically, early-onset AD patients are often
not included in drug studies because of the young age. Approximately 13% of the
cases of early-onset alzheimer¡¯s are familial AD[23],
that is, known to be entirely inherited. People with Downs¡¯ syndrome[24]
or other autosomal-dominant inheritance are particularly at a risk for this
form of AD. There are even the rarest of rare cases of non-familial early-onset
AD that thrive in people of 30¡¯s or 40¡¯s.
Late-onset alzheimer's
Late-onset alzheimer¡¯s is the most prevalent type of AD which
accounts for about the rest 90% of the cases, and usually occurs after age 65.
Late-onset AD strikes almost half of all people over the age of 85 and may or
may not be hereditary. Late-onset dementia is also called sporadic AD[25],
in which genetic and environmental differences may act as risk factors,
exclusive of autosomal-dominant inheritance. The disease can also be associated
with a genetically defected chromosome 14, to which late-onset AD is not
related.
Clinical
Symptoms of Alzheimer¡¯s disease
The 2011 proposed criteria and guidelines for diagnosis of AD[26-29]
suggest that AD begins 20 years or more before the occurrence of symptoms
referred as the preclinical stage of AD or asymptomatic stage of AD.
People seem to be free of any symptom but toxic changes start occurring in the
brain by this time. Since there is no effective treatment to delay onset or
prevent the disease, the focus has now shifted to identify and treat AD during
the long preclinical stage.
The destruction to nerve cells and tissues starts from the cerebral
cortex. It is the region of the brain responsible for high-level brain
functions such as consciousness, memory, language, reading and intelligence,
which starts shriveling up. According to the results[30], AD
patients¡¯ oral reading is marked by reduction of speech and articulation rates,
high number and proportion of pauses, and poor effectiveness of phonation time.
All parts of the visual system may be affected, including the optic nerve and
the retina[31].
The area of
the cortex, mainly hippocampus, which is responsible for the formation of the
new memory, begins to shrink[32], leading to short term memory loss,
the first warning signs of cognitive loss, demarcated as the early stage of AD.
The condition is sometimes more pronounced with mild cognitive impairment
(MCI). MCI, also called prodromal stage of AD, is the transition stage
between preclinical stage and early AD. A trend of a slight increase of
cerebral blood flow in both hippocampi and the posterior cingulate gyrus has
been noticed in MCI patients with a decrease in AD patients[33]. The
MCI stage of the disease is detected through cognitive tasks like the
mini-mental state examination and computerized screening instruments[34].
At this stage of the disease, memory deficit becomes serious enough to be
noticed by the subject or other people but at the same time does not hamper
daily life or independent function.
Progression of
Alzheimer¡¯s aggravates memory loss and evidently impairs other cognitive
abilities, such as reasoning or judgment, vision, language and word-finding,
leading to dementia. Memory loss and confusion grow worse, and people
begin to have problems identifying family and friends. They may have difficulty
to grasp new things, perform daily tasks or manage with new situations.
People are
often diagnosed in the dementia stage[26]. The incidence of dementia
and AD is considered to be associated with neuropsychiatric symptoms[35]
and therapeutically targeting the latter might retard the conversion of MCI to
dementia. Behavioral or non-pharmacologic treatment may represent another
effort towards reduction of dementia risk in AD patients[36,37]. A
study revealed the existence of a poor perception of emotions in AD subjects[38].
A distinct pattern was observed in visual and auditory-verbal perception,
whereas only the verbal modality seems to be relatively preserved. Thus,
strengthening of emotional prosody can be used as a communication support
between the patient and care-givers.
Problem of
apathy, hallucinations, paranoia and delusions[39] make the patients
more impulsive. These symptoms occur in approximately 50% of AD patients,
indicative of a more severe phenotype. The risk for psychosis in AD is
genetically mediated, as revealed by studies on familial aggregation of AD and
psychosis[40]. Baseline inferior temporal and supramarginal cortical
thinning are predictive of worsening apathy and hallucination over time[41].
Actigraphy can prove to be a fruitful complementary measurement in the clinical
diagnosis of apathy related to AD[42]. Delusions are clinically and
neurobiologically related to memory deficits but partially. Likewise
hallucination, delusion in AD, is linked with dysfunctioning of specific
frontal and temporal cortex[43].
Then, in the early
stages of AD, the alterations in plaques and deposition of tau proteins
start taking place. A dramatically high loss of nerve cell and synapse are
identified hallmarks of Alzheimer¡¯s brain abnormalities, which are suspected to
be caused due to senile (neuritic) plaques and tangles. Plaques are formed when
abnormal clusters of protein pieces called amyloid-beta (A¦Â) clump up together
between neurons. Plaques and/or tangles may destroy vital cell transport system
and hinder cell-to-cell signaling at synapses. Post-mortem results of the human
hippocampus, and the CA1 region in 3xTg-AD mice revealed that these alterations
are administered by hippocampus[44].
The
progression of AD is studied using the patterns in which these plaques and
tangles are spread through the cortex. The basis for these changes is unknown,
but preferably a combination of factors commences common biochemical and
physiologic pathways that finally lead to nerve cell dysfunction and death[45].
In the advanced stage of AD, plaques and tangles escalate throughout the
brain, and brain tissues shrivel dramatically. Patients have the highest levels
of A¦Â peptide and neurofibrillary tangles in this stage. They become bedridden
and cannot communicate, completely becoming dependent on care-takers.
Alzheimer¡¯s
Pathogenecity and Therapeutic Perspective
1. Genetics
Apolipoprotein E4 (APOE4) genotype is the profound genetic risk factor
for late-onset AD. On chromosome 19, the APOE gene has three common alleles: ɛ2, ɛ3 and ɛ4. Apolipoprotein
E (APOE) ¦Å4 alleles escalate the risk for late-onset AD and mitigate the age of
AD onset[46]. Cohorts with at least one APOE ɛ2 provide some
protection against AD and show better performance on neuropsychological
measures as compared to those without an ɛ2 allele[47]. On the
other hand, APOE ɛ3 may play a
neutral role in the disease i.e. neither increasing nor decreasing the risk[48].
The findings of Yang et al[49]. suggest that bone marrow
transplants-derived APOE3-expressing cells may have better ability to reduce
the behavioral and neuropathological changes in experimental AD as compared to
those that express APOE4.
Sherva et
al[50] reported the first genome-wide association study to
investigate the rate of cognitive decline in a sample of AD subjects with
longitudinal measures of cognition. Their data suggested the association of SPON1,
a protein-coding gene, with the interindividual variability existing in the AD
trajectories. The gene product plausibly binds to amyloid precursor protein
(APP) inhibiting its cleavage by ¦Â-secretase.
Neurodegeneration and AD might be advanced by chronically elevated level
of the RCAN1-1 protein[51]. The
methionine/valine polymorphism in the PRNP gene harbors the vulnerability of
the disease[52]. Tiedt et al[53] recognized a new
mutation in a male patient with early onset familial AD, which resulted in the
deletion of a leucine at codon 174 of PSEN1. DNA sequencing[54]
exhibited a heterozygous nucleotide transition (c.824C > T) in exon 8 of
PSEN1, leading to change in alanine to valine at codon 275 (Ala275Val). Another
gene family TREML2 may also foster risk alleles for AD; mainly the genes,
TREM2-p.R47H and TREML2-p.S144G are associated with increased and reduced risk
for AD, respectively.[55] Coding variations in ADAM10 have also been reviewed
in familial AD[56]. A recent meta-analysis of 74,046 individuals
identified 11 new susceptibility loci for AD and discussed some already known
loci, which include CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B,
SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP[57].
Green et al[58]
observed the combined effects of two Alzheimer¡¯s risk alleles, APOE-¦Å4 and
CLU-C, which decrease brain activity in the medial temporal lobe, a brain area
affected early in AD. They used assays which are known to track an early AD
intervention, executive attention assays during functional magnetic resonance
imaging (fMRI) in young adults, pointing to the necessity for establishing
early biomarkers of increased AD risk. The TT allele of progranulin
polymorphism rs5848 is also related with increased chances of AD, suggestive of
the significant role of progranulin gene in AD progression[59,60].
Single nucleotide polymorphisms were not found to be related to AD as probed in
a Polish population[61].
2. Protein
Aggregation
Aggregation of protein plays an important role in pathogenesis of most
of the neurodegenerative diseases, including AD. In the process of protein
aggregation[62], a monomeric unit interacts with another monomeric
unit of the same protein forming dimers, oligomers and even multimers. This is
accompanied with conformational changes in the 3-D structure of the protein and
formation of beta-strands. In such a way, the size of aggregates keeps on increasing
and this is normally taken care by complex cellular quality control mechanisms
of the body. However, under certain adverse circumstances, like high protein
concentration, complex interactions with other peptidic chains or specific
cellular environment, an undesirable subset of protein may aggregate
intracellularly or extracellularly[63].
In order to
stabilize the aggregated structures, the interaction between beta-strands and
beta-sheets takes place, leading to extracellular precipitation of insoluble
amyloid fibrils or senile plaques within beta-sheets, subsequently causing
neurotoxicity[64,65]. The formation of amyloid plaques is one of the
two types of protein aggregation in the brain that characterizes AD pathology
and the other is intracellular neurofibrillary tangles. Neurofibrillary tangles
are composed of highly phosphorylated forms of the microtubule-associated tau
protein[66]. Tau proteins are often found in close proximity to
amyloid deposits[67,68] and have been suggested as vital mediators
of amyloid plaque induced neurotoxicity.
Currently, AD
is defined by the regional presence of neuritic plaques and neurofibrillary
tangles in the brain along with the deposition of A¦Â aggregation. Hence, it is
justified to speculate that any kind of event that is capable of kicking off
the biophysical process of tau and A¦Â aggregation results into AD[69].
The following topics under this section describe a number of recent studies
related to the two major AD pathologies - amyloid and tau hypotheses supported
with a brief framework of the biochemistry involved.
2.1 Formation
of Amyloid Plaques ¨C Amyloid Hypothesis
Long before enzymes appeared, amyloid plaques have been believed to
catalyze metabolic reactions of life[70]. Amyloid plaques are found in
the extracellular region and are basically composed of a ~4 kDa protein,
specifically A¦Â protein. A¦Â protein is the primitive component of the amyloid
plaques formed in the brain tissues of AD patients[71]. The exact
mechanism of toxicity of amyloidogenic proteins is not yet known. In a recent
structure-function study of amyloid pores in AD[72], it was found
that monomers adopt the U-shaped, ¦Â-strand-turn-¦Â-strand pattern as a usual
feature of beta amyloid organization.
As per in vivo
and in vitro studies, A¦Â deposits are toxic to hippocampal and cortical neurons[64,73,74].
Amyloidogenic proteins, characterized by their ability to form fibrillar
aggregates with ¦Â-sheet configurations, also play an important role in several
other neurodegenerative diseases. A larger A¦Â burden is found in the brain of
living early-onset AD cohorts as compared to late-onset AD cohorts[75],
which is in agreement with those from postmortem studies. The indirect
proportionality between A¦Â burden and age-at-onset is possibly related with
aging-associated decline of brain or cognitive reserve and with
aging-associated increase of brain susceptibility. On the other hand, Castello
and Soriano[76] suggested that accumulation of A¦Â is neither
necessary nor sufficient to initiate pathogenesis in sporadic AD.
A¦Â is produced
by the action of two aspartyl proteases, ¦Â- and ¦Ã-secretases on amyloid
precursor protein (APP)[77-79]. Firstly, ¦Â-secretase cleaves APP to
generate the N-terminal of the protein, which is then followed by the action of
¦Ã-secretases to release A¦Â[80,81]. There are two basic forms of A¦Â
which depend on the number of amino acid residues produced, which is either A¦Â40
or A¦Â42. The other minor fragments of peptides, A¦Â37 and A¦Â38 have also been
identified and analyzed by liquid chromatography-MS and immunochemical methods[82].
A consistent
increase in the levels of A¦Â42 is comparably more common than its counterpart,
A¦Â40. A short-lived increase in the amount of A¦Â42 is observed in cohorts with
major head injury, a recognized AD risk factor[83]. An elevated
proportion of the 42-amino acid form is enough for progression of early-onset
AD but this is not the case for the more common sporadic forms of AD. In
autosomal-dominant familial AD, deposition of amyloidogenic protein elevates
with AD-causing mutations within presenilin (PS), especially PS1 and PS2 genes
and APP[84]. Inherited mutations in PS1 and PS2 increase the ratio
of A¦Â42 to A¦Â40, which leads to very early and hostile forms of AD.
The main
constituents of A¦Â plaques, A¦Â40 and A¦Â42, associate to form abnormal
extracellular deposits of amorphous aggregates and aggregated forms
(protofibrils and fibrils)[85]. Fibrillary aggregates of A¦Â may
enhance the effect of oligomers and protofibrils by creating mechanical
barriers for diffusion, sprouting and migration of cells in brain parenchyma[69].
However, Walsh and Selkoe have shown that A¦Â dimers and trimers have more
neuronal toxic effect and synaptic loss as compared to fibrillary proteins[86].
Since A¦Â seems to be the main culprit in the AD pathology and A¦Â oligomers are
the roots of neurotoxicity in AD[87,88], the amyloid hypothesis has
become the major focus of much AD research. The amyloid pathology can be
targeted either by inhibiting the enzymatic action of one of the secretases (¦Â-
and ¦Ã-secretase) or by removal of A¦Â deposits using antibodies[89].
The
carboxyl-terminal cleavage of APP to form isoforms of A¦Â40 and A¦Â42 results
from ¦Ã-secretase activity. Many potent small molecules have been developed to
inhibit ¦Ã-secretase to reduce the formation of A¦Â40 and A¦Â42[90-94],
but, unfortunately, ¦Ã-secretase not only targets APP, the main precursor of A¦Â,
but also cleaves Notch receptors, which are crucially important for normal
growth[95,96]. Besides, potent ¦Ã-secretase inhibitors have several
side effects like serious immunological and gastrointestinal problems[97].
Such drawbacks have directed researchers towards the development of ¦Ã-secretase
modulators[98]. The function of these modulators is to either
specifically cleave APP without affecting Notch cleavage or modify the cleavage
of APP by ¦Ã-secretase to favor the production of A¦Â40 over that of A¦Â42[99-104].
Such drugs include non-steroidal anti-inflammatory drugs (NSAIDs) such as
ibuprofen[34] and drugs that interact with the ATP-binding cassette
of PS1 near the active site of the enzyme[105].
The serious
target-related side effects of ¦Ã-secretase have aroused interest in the
possibility of targeting ¦Â-secretase for AD treatment. It is worth mentioning
here that the activity of a single protease, ¦Â-secretase 1 (BACE1) is involved
in ¦Â-secretase cleavage of APP[81,106-109] and inhibition of BACE1 activity
has no serious target-related issues[110]. BACE1 inhibitors can block A¦Â production, retard the cascade of
amyloid pathology and prevent AD related memory deficits in mice brain[111-114].
However, the struggle is still on to seek effective BACE1 inhibitors that are
active in CNS. The problem lies in the large active site of BACE1, which calls
for identification of large molecules as potent BACE1 inhibitors. Such heavy
molecular weight molecules usually have poor blood brain permeability and are rarely
stable. Some studies[115-124] also suggest the role of BACE1 in
cleavage of alternative substrates like ¦Á2,6-sialyltransferase, interleukin-1
receptor II, P-selectin glycoprotein ligand-1, APLP2, lipoprotein and
voltage-gated sodium channels, and these may play physiological roles in
humans. Despite the aforementioned drawbacks to the approach of secretase
inhibition, ¦Ã-secretase inhibitors, ¦Ã-secretase modulators and ¦Â-secretase
inhibitors continue to actively follow as drug targets for AD therapy in the
hope that the concluding benefits might outweigh the risks[63].
The second
approach to address the A¦Â menace is to target the degradation of the
aggregated protein or the aggregates. For this purpose, immune system
manipulation is the sought after therapeutic approach for AD to dramatically
improve cognitive deficits and/ or reduce A¦Â and plaque pathology. Although the
desired results have been obtained on passive transfer of A¦Â-specified
antibodies in APP-transgenic mice, clinical trials on humans were stopped due
to the development of sterile meningocephalitis in a subset of individuals[125].
However, A¦Â immunotherapies still have hope as monoclonal A¦Â antibodies, since
the humanized monoclonal antibody, bapineuzumab (¡®bapi¡¯), from the Élan-Wyeth
pharmaceutical company significantly delayed cognitive decline in some cohorts[126].
Immunotheraupists also believe that the approved treatment for immune
deficiencies and autoimmune disorders can be effectively used in A¦Â clearance
and cognitive improvement in AD patients[127,128].
The
intracellular A¦Â might also play a central role in the pathophysiology of the
disease. Although the A¦Â plaques are extracellular lesions, they may mediate
their toxic effects inside the neuron if soluble oligomers are the principal
toxic species[63,129]. Most of the A¦Â is excreted from the cell
through the secretory pathway. On the contrary, there are evidences that
intracellular A¦Â plays an important role in AD pathology. The disease-related
isoform of A¦Â, A¦Â42, appears to be more vulnerable to intracellular
accumulation relative to A¦Â40. Intracellular A¦Â mounts more frequently in the
highly-affected region of the Alzheimer¡¯s brain, i.e. entorhinal cortex and
hippocampus[130].
The
aggregation of amyloidogenic proteins damages brain mitochondria, which causes
neuronal dysfunction. Mitochondrial beta-amyloid plays a critical role in the
development of AD as it binds to beta-amyloid-binding alcohol dehydrogenase, a
mitochondrial enzyme[131]. It also induces oxidative stress[132]
leading to increase in the levels of lipid peroxidation products. This may
trigger neurodegeneration by causing oxidative dysfunction of essential
energy-related complexes in mitochondria[133].
The
intracellular A¦Â gets bound to heme groups in mitochondrial membranes impairing
electron transport chain and loss of respiratory function. The experimental
affirmation of such oxidative stress leads to the basis for treatment of AD
with antioxidants[134]. Also, the profound genetic risk factor, ¦Å4
allele of APOE4, elevates intracellular A¦Â[135] whereas increased
synaptic activities reduce it[136]. A¦Â immunotherapy can be used to
address the reduction of intracellular A¦Â[137,138].
Also,
Memantine combined with vitamin D may avert degeneration of nerve fibers
triggered by A¦Â[139] and can be applied to prevent the onset of AD.
Memantine is accepted for treatment of moderate to severe AD. Recently,
proline-rich polypeptide-1 was tested as a neuroprotective agent on A¦Â25-35
animal model of AD and was concluded to be one of the effective preventive
agents to fight against neurodegenerative disorders[140].
Interestingly,
an executable mathematical language, Maude was used to write a computational
model to simulate and logically analyze the system it models. The amyloid
hypothesis was used as the basis of the AD model[141]. On analyzing
the model, it was found that A¦Â regulation can be interrupted through the
interaction of pathological processes such as cerebrovascular insufficiency,
oxidative stress, and inflammation. Lately, what experiments and computer
simulations can offer us about A¦Â and its link to AD has been reviewed[142].
In order to understand this link, the usage of computational techniques to
study the A¦Â conformational properties are encouraged, keeping in mind the
challenges and limitations inherent to the current set of experimental
techniques.
2.2 Formation
of Neurofibrillary Tangles ¨C Tau Hypothesis
The neurofibrillary tangles of tau protein observed in AD brains are
likely to have been deposited after changes in A¦Â metabolism and initial plaque
formation[143-145]. Discovery of tau protein goes back to some 40
years. The normal functioning of the neurons is dependent on tau protein as it
stabilizes microtubules by promoting tubulins assembly. Microtubules, a major
component of the neuronal cytoskeleton, is responsible for normal morphology
and gives structural support to the nerve cells[146]. Tau protein
that can regulate tubulins assembly into microubules is in the phoshorylated
form. The coordinated action of kinases and phosphatases on tau protein further
assists the tubulins assembly[147-148]. Under AD pathological
conditions, abnormal phosphorylation of tau protein takes place. This limits
the binding capacity of tubulins to disorganize microtubules. Also, self
polymerization and aggregation of tau into paired helical filaments[149]
progressively leads to formation of neurofibrillary tangles inside the neurons[150-152].
A¦Â-like biophysical mechanism of protein aggregation is applied for the
production of tau-derived neurofibrillary changes (neuropil threads,
neurofibrillary tangles, neuritic plaques). Like the toxicity of A¦Â, toxic
intermediates of tau (oligomers and fibrillary tau protein) cause toxicity at
the cell biological level.
New
perspectives on the role of tau in AD and its therapeutic implications have
been actively pursued in a review[153]. In AD, tau protein fails to
keep the cytoskeleton well assembled in the axonal process as it fails to bind
to microtubules. This abnormality is advanced by prominent modifications in the
conformation of the tau native structure and tau misfoldings[154-156].
Abnormal post-translational modifications seem to be the main reason of this
abnormality[157,158]. In Alzheimer¡¯s, fibril inclusions start from
the entorhinal cortex, progressively damage the hippocampus, and ultimately the
neocortex[159]. As these regions of brain are essential for learning
and memory, progression of tangles pathology is victimized with cognitive loss[160].
The density of neurofibrillary tangles distributed along the entorhinal cortex,
hippocampus and neocortex has been correlated with the degree of dementia in AD[161].
The
nonfunctionality of tau protein has been proposed to be caused due to abnormal
phosphorylation, also called hyperphosphorylated state. Accumulation of
post-translationally phosphorylated tau proteins takes place early in neurons,
even prior to formation of neurofibrillary tangles. In the hyperphosphorylated
state, the tau protein is deprived of its biological activity. In AD, the
hyperphosphorylation[162,163] might be a result of upregulation of
tau kinases[164] like GSK- 3¦Â, cAMP-dependent protein kinase,
cyclin-dependent kinase 5, and calcium/ calmodulin-dependent kinase II and/ or
downregulation of tau phosphatases, which include PP1, PP2A, PP2B, and PP2C[165].
It has been proposed that tau hyperphosphorylation occurs prior to its cleavage[166,167]
and formation of neurofibrillary tangles follows tau cleavage[168].
The former has been confirmed by in vitro studies of ethanol-induced neuronal
apoptosis in the developing mouse brain[167,169]. The other proposed
reasons for the loss of normal functioning of the tau protein can be acetylation,
nitration, glycation, truncation, ubiquitination and conformational changes[154,170-179].
Tau
hyperphosphorylation and misfolding take place both at presynaptic and
postsynaptic terminals. The abnormal post-translationally modified tau is enriched
in synaptoneurosomal fractions. The accumulation of hyperphosphorylation tau
oligomers at human AD synapses is associated with increased ubiquitinated
substrates and proteasome components that may disrupt synapses in AD[180].
Besides this, considerable hyperphosphorylation and misfolding of synaptic tau
take place amongst non-demented elderly, signifying synapse to be one of the
first subcellular compartments affected by tauopathy[181].
In a healthy
neuron, over ten-fold excess of tau is in the microtubule bounded form[182,183].
On the other hand, in AD affected neurons, hyperphosphorylated tau does not
bind to tubulins, which leads to disintegration of microtubules. The
disintegration of microtubules affects the neuronal transport system and affects
the distribution of mitochondria. The disrupted distribution of mitochondria in
the peripheral region of axon can decrease glucose levels, lipid metabolism and
synthesis of ATP and loss of Ca2+ homeostasis[184],
leading to a neuronal degeneration state called ¡°dying back¡± of axons. Synapses
are also dependent on mitochondria for the energy required for its regular
functioning[185] and tau protein abnormalities interrupt
mitochondria from providing energy to synapses causing synaptic loss[186].
Tau proteolytic
cleavage can be considered as another possible mechanism that may promote tau
protein aggregation[187-189]. Unfortunately, the enzyme that is
associated with the proteolytic cleavage of tau is not clearly known. Some
findings suggest association of aberrant proteolysis even with programmed cell
death[190,191]. The correlation of apoptosis and associated caspases
with the neurodegenerative process in AD shows the proliferation of apoptotic
cells in the protein aggregation prone areas of the brain[192-194].
Caspases, the cystein proteases, cleave ASP residue in the canonical consensus
sequence on the carboxyl terminal of molecule. Caspase enzymes, especially
caspase3, participate in a proteolytic cascade to kill cells via apoptosis[195].
They also play a vital role in A¦Â-induced neuronal apoptosis[196]
and are activated in apoptotic neurons in AD[197].
Tau is also
found in the cerebrospinal fluid (CSF)[198] and increased level of
tau is an AD biomarker. There are numerous pathways that have been hypothesized
to explain the presence of tau in the CSF. Tau might have passively released
from dead or dying tangle-bearing neurons or actively secreted and transferred
between neurons through synapse[199]. Although the intercellular
transfer of tau is of great interest and vital in tau pathology, the exact
mechanism of neuronal internalization of tau remains a moot question. However,
it is often hypothesized that the mechanism depends upon the nature of the tau
intermediate involved, say monomers[200,201], small soluble
oligomers[202] or aggregates[203]. In AD, the elevated
levels of tau phosphorylated on T181 has been found in human CSF[204],
suggesting that tau phosphorylation may be modified extracellularly.
Since it is now understood that the progression of tau pathology in AD
is marked by interneuronal transfer of tau, suppressing this transfer may have
an impact on AD pathology. Also, tau pathology causes synaptic loss and
subsequent cell death; thus AD-related cognitive decline may be improved by preventing
intercellular tau transfer. The therapeutic strategies implemented in this
context are blocking tau release, reducing tau accumulation or extracellular
oligomerization or preventing uptake of tau by neighboring neurons[199].
3 Cholinergic
Deficiency
Some of the demential neuropsychiatric symptoms, such as hyperactivity,
depression, apathy and psychosis, may render central cholinergic deficiency
syndrome[205,206]. Cholinergic deficiency syndrome is the reduction
in the synthesis of a neurotransmitter, acetylcholine[207], which is
a well-known feature associated with AD[208]. The
acetylcholinesterase enzyme is involved in the breakdown of acetylcholine by
hydrolyzing it. The accessibility of acetylcholine can be increased by using
acetylcholinesterase inhibitors which inhibit the acetylcholinesterase from
hydrolyzing acetylcholine. Tacrine, rivastigmine, donepezil and galantamine are
the four approved acetylcholinesterase inhibitors[209,210], but none
of these can delay or halt the disease progression. In fact, for half of the AD
subjects with milder forms of the disease, these drugs remained effective for
just 6-12 months[211]. Therefore, the researchers are more
interested in targeting A¦Â and tau proteins[187,212,213] and BACE[214].
An endogenous
neurotrophic-factor protein, termed as nerve growth factor (NGF) has a
potential to restore function and to avoid degenerating cholinergic neurons in
AD, but offers a long-standing delivery obstacle. Recently, ten AD patients
were successfully administered with genetically engineered gene-therapy vector
adeno-associated virus serotype 2 delivering NGF (AAV2-NGF [CERE-110]) to the
nucleus basalis of Meynert[215]. The latter was found to be safe and
well-tolerated for two years without any evidence of accelerated decline.
4. Apoptosis
For proper functioning and to maintain constant size
of proliferative tissues, it is necessary for the older cells to die and make
way for new cells. Apoptosis, a stereotyped sequence of biochemical and
morphological changes, leads to ¡®programmed¡¯ cell death without adversely
influencing its neighbors[216]. Hence, it is also frequently called
¡°programmed cell death¡±[217]. In contrast to proliferative tissues,
neurons of an organism need to stay alive for the whole lifetime as they are
responsible for maintaining the function of cells with neuronal circuits.
Unfortunately, excessive death of neurons may take place, resulting in disease
or injury. For example, Alzheimer¡¯s disease involves the death of hippocampal
and cortical neurons[216].
Necrosis and
apoptosis are two ways by which cell death can occur. Apoptosis is a
programmed, smooth and tightly regulated physiological method required for
maintaining a balance between cell division and cell death. In contrast to
this, necrosis results in quick disruption of the cellular mechanism and
non-physiological disintegration of the cells. A combination of both apoptosis
and necrosis may occur in contributing to neurodegeneration in AD. Both may
overlap or occur sequentially[217].
Occurrence of
apoptosis in Alzheimer¡¯s came into the picture in 1993 when two research teams,
Carl Cotman's at the University of California, Irvine, and Gianluigi Forloni's
at the Institute of Pharmacological Research in Milan, Italy, showed that A¦Â,
which accumulates in the brains of patients suffering from AD, leads to the
death of cultured neurons by apoptosis[218]. There have been many
other hints regarding occurrence of apoptosis in AD[197,219-223].
Apoptosis
leads to the cleavage of the AD associated vital proteins, APP and presenilins,
which are also commonly referred to as ¡®cell death substrates¡¯, as the process
ultimately results in cell death[224]. Presenilin mutations also
disturb calcium homeostatsis in the endoplasmic reticulum such that neurons are
sensitized to apoptosis and excitotoxicity[225].
Activity of
the apoptosis-associated family of cysteine proteases named caspases[226],
has been found in neurons related with amyloid deposits in the brains of people
suffering from AD[216]. Gervais et al[196]
suggested that APP is cleaved by capsases. They proposed that this may be an
early event that facilitates the production of A¦Â, suggesting the strong link
that apoptic cell death might have with deposition of A¦Â. The predominant site
where this proteolysis mediated by caspase occurs is within the cytoplasmic
tail of APP. The cleavage occurs in hippocampal neurons in vivo, which is
followed by acute excitotoxic or ischemic brain. Based on sequence homology,
the caspases family of proteases is classified into three subfamilies:
caspase-1 (ICE), caspase-2 (ICH-1), and caspase-3 (CPP32).[226] As already
mentioned, Caspase-3 shows a marked elevation in neurons that are dying in
Alzheimer¡¯s disease, implying caspase-3 to be the predominant caspase involved
in APP cleavage[196]. Caspase activation is thus a prerequisite of
apoptosis[217]. Different cellular substrates for caspases have been
described. For example, an essential cellular protein, ICAD, which is an
inhibitor of caspase-activated deoxyribonuclease (CAD or DFF45), is cleaved by
caspase, which actually begins DNA fragmentation[227]. Capases
attack the main essential structures of the cell by cutting off contacts with
surrounding cells, reorganizing cytoskeleton, shutting down replication and
repair of DNA, interrupting splicing, disrupting nuclear structure and
disintegrating cells into apoptotic bodies[228]. Caspase activation
may also involve signaling pathways such as apoptotic triggers like toxins,
death receptors like Fas/CD95 and intracellular stress conditions[217].
Mutations in
presenilins alter ¦Ã-secretase cleavage of APP at the C terminus of A¦Â. In one
pathway, presenilin mutations increase production of A¦Â directly, which induces
apoptosis and activation of caspase. Caspase cleavage of APP further
facilitates greater A¦Â production, resulting in a vicious cycle that involves
apoptosis and A¦Â generation. In the second pathway, presenilin mutations first
activate caspase which cleaves APP and results in increased A¦Â production. Both
pathways relate apoptosis and caspase activation with increased generation of A¦Â[224].
Changes in
expression of apoptosis-related genes like the Bcl-2 family of regulator
proteins, Par- 4 and DNA damage response genes and increased DNA damage have
also been found to be linked to accumulation of amyloid deposits in AD brains[216].
Bcl-2 of the Bcl-2 family of regulator proteins is anti-apoptotic, whereas
some, like Bax, Bad, and Bak, are pro-apoptotic in their function. For the
survival of individual neurons, balance of pro-apoptotic (Bax, Bak and Bad) and
anti-apoptotic (Bcl-2 and Bcl-xL) proteins may be essential. Neurons that have
high levels of Bak and Bad, and normal or low levels of Bcl-2 and Bcl-xL die,
while increased levels of Bcl-2 and Bcl-xL inhibit apoptosis[226].
Another major
pathway that leads to activation of caspase is the release of cytochrome c from
mitochondria. Assembly of apoptosome, a large proteinaceous complex made up of
an oligomer of Apaf-1 and procaspase-9, is controlled by cytochrome c in the
cytosol. When this complex is formed, caspase-9 is activated, which further
activates other caspases[229]. It lies in the space between the
outer and inner membranes of mitochondria, where cytochrome c resides in
healthy cells. It has been proposed that members of the Bcl2 family, such as
Bad, Bak, Bax and Bid, cause cytochrome-c release[230,231]. These
proteins have been reported to form pores in the outer membrane through which
diffusion of cytochrome c occurs[232]. In fact, other apoptotic
proteins and several caspases and apoptosis-inducing factor might also translocate
from mitochondria to the cytosol[229]. Apart from activating caspase
and inducing apoptosis, release of cytochrome c may also result in loss of
oxidative phosphorylation and production of reactive oxygen species, which may
lead to cell death[233,234].
The
clarification of the mechanism of apoptosis promises to the discovery of
therapeutic drugs that would help in prevention and therapy of AD[217].
In recent years, much attention has been devoted to identify drugs that control
apoptosis, but the results have been unsatisfactory. Thus, it is necessary to
find novel targets for the same[235].
5
Neuroinflammation
Inflammation or inflammatory response is an inherent part of the body¡¯s
defense mechanisms to fight against numerous threats, including injuries and
infections. Inflammations could be of three types: inflamm-aging,
metaflammation and peripheral inflammation. Inflamm-aging is a term used to
describe a condition when the immune system runs amiss with age, damaging aged
tissues. Sometimes the response may be less protective and more harmful due to
a low-grade and chronic form of inflammation called metainflammation.
Inflammation may also exist due to damages affecting nerves, causing peripheral
inflammation.
These
inflammations can contribute to the AD onset by increasing the toxic levels of
A¦Â protein[236]. It is believed to be caused by malfunctioning of
blood brain barrier transporters, which then fails to push the accumulated A¦Â
proteins from the brain into the blood. These evidences suggest that
proinflammatory cytokines, the cell signalling proteins which promote
systematic inflammation, should be considered as therapeutic targets or
relevant biomarkers in psychiatric disorders[237,238].
Neuroinflammatory and neuroregenerative processes occur in the early
stages of AD pathology[239]. In advanced stages of AD, neocortex
exhibits upregulation of inflammatory mediators. This takes place as a
regenerative response to the deposition of amyloidogenic proteins. A¦Â is
considered as a foreign substance by the immunity system of the body which in
turn generates anti-A¦Â antibodies. The removal of A¦Â by anti-A¦Â antibodies
leads to clearance of the A¦Â deposits with subsequent reduction of the
dystrophic neurites as found in transgenic APP mice.
NSAIDs tamper
inflammation by inhibiting the main mediators of CNS neuroinflammation such as
cyclooxygenase-mediated signaling pathways including prostaglandins. Since
neuroinflammation has become an important pathological hallmark of AD, NSAIDs
are associated with reduced incidence of AD[240], but their
administration has adverse cardiovascular side-effects. Thus more targeted
exploitation of downstream prostaglandin signaling pathways must be addressed
to prevent or therapeutically intervene AD[241].
A two-photon
excitation microscopy displays that infiltrated neutrophils in the brain
migrate to brain A¦Â plaques[242]. The study suggests a possible
influence of these immune cells on the progression of AD, especially in
relation to brain inflammation. Fingolimod, a new oral immunosuppressant used
to treat a neuroinflammatory disease, multiple sclerosis, may provide
therapeutic effects in patients with AD, by up-regulating neuronal
brain-derived neurotophic factor[243].
Antidiabetic
drugs affect brain metabolism like neuroinflammation and neuroregeneration.
This suggests the contribution of these drugs to the evolution of disease
modifying treatments for neurodegenerative diseases[236]. Ginseng
Rb1 is also found to reverse the changes in a number of direct or indirect
hippocampal neuroinflammation markers, indicating that this could be a
potential way to develop anti-aging drugs[244].
6 Miscellaneous
Insulin, a key factor of diabetic pathogenesis, is involved in
essential pathways of learning and memory in CNS and thus contributes to the
development and progression of AD in aging patients with diabetes[245].
In early sporadic AD pathology, abnormal brain glucose metabolism and insulin
signaling have been reported to play a crucial role[246]. Over two-third
of AD cohorts were clinically indentified with impairment of glucose. It is
hypothesized[247] that AD, clinically and pathologically, presents a
metabolic form of diabetes on the brain and would also contribute to the
pancreatic and beta-cells degeneration, leading to diabetes. Using a positron
emission tomography (PET) probe of regional glucose utilization in the brain,
it was suggested that severe energy deficiency for preclinical AD and MCI
patients is consistent with the progression of AD[248].
Malfunction in
the iron biomineralization undertaken by ferritin may be a pivotal factor in
development of AD[249]. The amount of nanocrystals of magnetite (Fe3O4)
intrinsically found in the human brains is generally increased in the
Alzheimer¡¯s brain[250].
Correia et
al[251] carried out thorough research in autopsy brain tissues
from AD cohorts, AD animals and other cellular models. They found that multiple
malfunctioning takes place in mitochondria during the course of the disease.
The mitochondria isolated from lymphocytes of patients with MCI have been found
to undergo an increase in oxidative stress. On correlation with varying levels
of a number of vitamin E components, an increase in oxidative stress markers in
the peripheral system was observed[252]. This may potentially
reflect brain damage and can also serve as a potential biomarker in AD
pathogenesis.
Preventions
The potential misconceptions related to risk and protective factors can
be targeted with tailored educational endeavors. It was found in a study that
older and middle-aged adults are concerned about their AD risk status and
believe that initiatives can be taken to reduce disease risk[253].
At present, there is no effective preventive measure for AD that comes with a
definitive affirmation to support these measures. Since global studies of
measures to avert the onset of AD or its delay have often produced inconsistent
results, the focus has now shifted to environmental proteomics associated to
the disease[254].
1.
Environmental Factors
Environmental factors such as ingestion of metals like lead[255],
iron and zinc[256] may also be associated with the development or
progression of AD. An imbalance in the levels of redox transition metals,
especially iron, copper, and other trace metals has been pinpointed by current
evidences[257]. They are present at higher levels
in subjects with AD and Parkinson disease while with other neurodegenerative
disorders, copper, zinc, aluminum, and manganese are involved.
Aluminium is a
neurotoxicant, which hastens brain aging but its extensively studied role in
the etiology of AD is still debated[258]. Some mechanisms
contributing to Al-induced neurobehavioral toxicity are noted in a review[259].
Metal ions, particularly copper(II), may contribute to the formation of amyloid
plaques and neurofibrillary tangles[260-262], which are the core
pathological hallmarks of AD.
2. Diet
The role of nutrition in regulating AD is not certain, though a lower
risk of AD is associated with a Mediterranean-type diet, coffee and moderate
alcohol consumption[263]. A Mediterranean diet and/or a food
combination, such as Souvenaid, seem to be the most effective approaches with
the least possible side effects to mitigate the progression of AD[264].
Epidemiologically, combination supplements rich in antioxidant vitamins may
also reduce the risk of AD. Retinoids, vitamin A-related compounds, reveal to
be capable therapeutic targets for AD treatment because of their capability to
affect the vital components of disease such as plaque formation, cholinergic
transmission, APOE expressions, cholesterol content and inflammatory
environment of the brain[265]. On the other hand, soy food
consumption may lead to the increasing incidence of AD and other dementias[266].
Additionally, vitamin D[267] and vitamin E related compounds[268]
such as ¦Ã- and ¦Á-tocopherols are also associated with health risks.
3. Others
The risk factors of AD onset differ enormously between the sexes. Women
are more prone to the development of AD than men and also more likely to be
informal caregivers for someone with AD or related dementias[15].
This entry focuses on the role of ovarian steroid hormones, especially
estrogens and progesterone, and their contributions to women¡¯s neurological
health[269]. As reviewed by Li and co-workers[270], brain
estradiol, a localized female sex hormone, has emerged as a therapeutic target
for preventing brain disorders and neurodegeneration. The benefits of estrogen
replacement therapy for cognitive functions and AD prevention, especially in
postmenopausal women, warrant attention. The biology of sex differences in
cognitive function is needed to be perceived in detail to provide insight into
AD prevention and development of personalized, gender-specific medicine[271].
AD
pathogenesis is associated with immoderate exposure to electromagnetic fields
from electrical grids, excessive alcohol intake, hyperhomocysteinaemia,
hypertension, hyperinsulinaemia and chronic anaemia[263]. A higher
risk of AD is associated with pesticides, smoking, traumatic brain injury,
obesity and high cholesterol levels in middle age. Along with the well-known
clinical and lifestyle risk factors, personality traits such as self-discipline
and depression are also associated with AD incidence[272].
AD
Biomarkers
1. Current
Biomarkers
Early treatment of AD patients may contribute to a small delay in their
institutionalization, resulting in notable cost savings[273]. To
improve both the diagnostic and prognostic accuracy of AD and to differentiate
it from other types of neurodegenerative dementia, the clinical symptoms and
signs are combined with biomarkers[274].
Throughout the
review, a number of known biomarkers have already been discussed. These
neurochemical indicators provide a reliable assessment of the disease and thus
need a summarization. Prior to the escalation of pathological changes, they
must be effectively diagnosed. Trzepacz et al[275] showed
that MRI[276] and amyloid PET neuroimaging[277] are the
best combination of biomarker modalities for predicting conversion of MCI to
AD.
The definitive
diagnosis of AD is only through brain biopsy or autopsy. Since CSF is in direct
contact with the brain, the molecular composition of CSF can also be a useful
source of information for diagnosing AD and other neurological disorders. CSF
levels of A¦Â40, A¦Â42, total tau (t-tau) and phosphorylated tau (p-tau) usually
form a part of the clinician¡¯s tool for accurate AD diagnosis. Soluble A¦Â
oligomers are also one of the diagnostic tools, as they are more synaptotoxic
for AD relative to A¦Â aggregates. Gene mutation in presenilins and APP is a
genetic predisposition to early-onset AD and can be a good predictor of the
same.
Different
phosphorylation epitopes, mainly tau181, can be detected by different
immunochemical methods. MCI to AD transition can be distinguished from stable
MCI with 90% and 100% sensitivity and selectivity respectively, with the help
of t-tau. On the other hand, p-tau181 shows a 80% sensitivity and 92%
specificity to discriminate AD from healthy cohorts[278]. Thus,
p-tau reveals a higher specificity than t-tau for diagnosing AD as compared to
other types of dementia. Also, several kinases and phosphatses, especially cdk5
and Gsk3¦Â, involved in the hyperphosphorylation modifications, characterize AD.
Upregulation
of the brain¡¯s innate immune response is another prime marker for neuronal
degeneration in AD, which results in inflammatory processes. Besides CSF,
amyloid and tau pathologies are ubiquitous in blood, saliva, skin and extra
brain tissues, and have moderately promising diagnostic values[278].
Now, let us discuss certain new potential biomarkers that have emerged to
predict the risk of AD progression.
2 New Potential
Biomarkers
The typical findings of established and new MRI procedures in healthy
aging, MCI, and AD are well documented[279-281]. Increased cortical
phase shift in AD patients demonstrated on 7-tesla T2*-weighted MRI is a
contemporary biomarker for AD, which may manifest amyloidogenesis in the early
stages[282]. Using multitask learning algorithms, Zhou et al[283]
analyzed MRI and cerebrospinal fluid data of the temporal patterns of
biomarkers in disease progression. They found that cortical thickness average
of left middle temporal, left and right entorhinal, and white matter volume of
left hippocampus play crucial role in predicting Alzheimer's disease Assessment
Scale cognitive subscale (ADAS-Cog) at any stage of the disease progression.
ADAS-Cog[284] is one of the cognitive measures designed for clinical
evaluation of cognitive status of the AD patients.
Welling et
al[285] postulated that antimicrobial peptides (AMPs) may be
labeled as a marker to target pathogens that play a role in aggregation of A¦Â
in the brain. AMPs can effectively penetrate infected cells and tissues beyond
many endothelial barriers, including blood brain barrier. So, cerebral
infections caused by environment influences such as viral or chronic bacterial
infections can be detected and diagnosed by AMPs.
Bad¨ªa and
co-workers[286] took the challenge to find the biomarkers of
early-onset familial AD, a boon to young healthy individuals at risk of AD.
Alzheimer¡¯s has been associated with oxidative stress. Lymphocytes from young,
healthy persons carrying at least one APOE¦Å4 allele, the strongest known single
genetic risk factor for AD, were considered. It was found that lymphocytes
suffered from reductive stress rather than oxidative, i.e., lower oxidized
glutathione and P-p38 levels and higher expression of enzymes involved in
antioxidant mechanism, such as glutamylcysteinyl ligase and glutathione
peroxidase. On the other hand, in the full fledged AD, the antioxidant
mechanism probably gets exhausted, the situation is reversed and oxidative
stress occurs. The findings of Bad¨ªas¡¯ group provided an insight into the early
events of AD progression that may help to find biomarkers of Alzheimer¡¯s at its
very early stages.
The largest
multiplexed plasma protein study till date for AD markers describes some novel
protein associations, and also validates some previously identified ones[287].
Prostate-specific antigen complexed to ¦Á1-antichymotrypsin, pancreatic
prohormone, clusterin, and fetuin B were found to be the strongest association
of protein levels with AD. Their findings provide strong affirmation that
quantities of these plasma proteins are truly associated with AD.
MicroRNAs
(miRNAs), endogenous small RNAs of 21¨C25 nucleotides, post-transcriptionally
regulate gene expressions. Recently, circulating miRNAs have been reported as
potential new biomarkers for neurodegenerative diseases and processes affecting
the central nervous system[288]. The study was carried out to
investigate the potential role of serum miRNAs as diagnostic biomarkers for AD.
Their results indicated that serum miR-125b may act as a fruitful noninvasive
biomarker for AD. Due to the easy availability of blood serum from AD patients,
the phospholipid alterations occurring in serum can be investigated as
promising biomarkers for diagnosis of AD[289]. These alterations are
indicative of membrane breakdown processes in pathogenesis of AD.
Labeling
tissue transglutaminase (tTG) as a biochemical marker for AD can be misleading[290].
In another report[291], the results of Wolff and co-workers were
criticized on the basis of the experimental conditions taken into account by
them and the overwhelming evidence in the literature which reports tTG to be a
promising biochemical marker of AD. Extracellular vesicles may also play a role
in initiation and progression of AD. Both normal and pathological cells release
extracellular vesicles which help in getting rid of unwanted cellular
substances. These vesicles are even functional in intercellular communication
like exchange of messenger RNAs, noncoding RNAs, and proteins between healthy
and/or pathological cells[292]. Perceiving the significance of the
role played by extracellular vesicles in AD initiation and progression, may
help in the discovery of new potential biomarkers.
A novel
concept of specific immune-sensing application on the controlled silanized
surface was proposed to quantify the biomarkers of AD in biological fluids[293].
The method employed grafting of the antibodies involved in the detection of AD
biomarkers over the silanized surface followed by evaluation of biological
activity using fluorescence microscopy. Machine learning methodologies are also
used to predict cognitive and disease states form neuroimaging data[294].
The progression of disease associated with aging, such as AD, is characterized
by gradual and continuous changes in the shape of the brain.
Most of the
contemporary shape analysis studies in AD and related dementia perform
statistics on the specific region of interests, already clinically known to be
affected. Recently, a multivariate analysis of diffeomorphic transformations of
the whole brain was presented[295]. The complex anatomical changes
were related with neuropsychological responses, such as clinical measures of
cognitive abilities, logical memory, audio-verbal learning, and measures of
executive functions. The proposed methodology may discover new patterns of
shape changes in the human brain that can help in envisaging progress of
disease in neurological disorders.
Conclusions
Unfortunately, the damages caused to the brain cannot be reversed with
ongoing treatments and the disease is incurable. At this time, there is no
treatment to slow down the rate of progression of the disease. So, it was
necessary to have new insights into the pathophysiology of AD. Courageous
efforts, cooperation and endurable management are needed to perceive the
incredibly complex AD, as aging population forms an important part of our
society. With increase in the lifespan, the number of patients with cognitive
diseases is only going to increase, and unless steps are taken right now to
slow down the progress of age-related diseases, AD may take on epidemic
proportions.
CONFLICT OF INTERESTS
The authors have no conflicts of interest to declare.
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Peer reviewer: Se
Bok Jang, Professor, Department of Molecular Biology, College of Natural
Sciences, Pusan National University, Jangjeon-dong, Geumjeong-gu, Busan
609-735, Republic of Korea.
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