FREE ESSAY ON AMYLOID PROTEIN MEDIATED NEURODEGENERATION

AMYLOID PROTEIN MEDIATED NEURODEGENERATION

Amyloid Protein Mediated Neurodegeneration
in Alzheimer's Disease
Alzheimer's Disease is a progressive, degenerative disease that affects the brain.
Individuals with AD experience a progressive and specific loss of cognitive function
resulting from the differentiation of the limbic system, association neocortex, and basal
forebrain. It is also accompanied by the deposition of amyloid in plaques and
cerebrovasculature, and the formation of neurofibrillary tangles in neurons. Alois
Alzheimer, a German doctor, diagnosed this disease for the first time in 1907. At that
time it was considered a rare disorder. Currently, this tragic brain disorder affects
approximately four million people; It is the most common type of dementia and the fourth
leading cause of death in the United States.
Many studies have been done and are still being conducted to determine the exact cause of
AD. The molecular and biological basis for the degeneration of neurons in AD is
incompletely understood. However, the APP(Amyloid Precursor Protein) and its proteolytic
fragments have been implicated more often than not and is the focus of most current
studies. 
Several lines of evidence have strengthened the amyloid hypothesis for Alzheimer's
Disease. The first being the identification of point mutations with the APP gene in
groups of patients afflicted with the familial forms of AD. Second, amyloid deposition
temporally precedes the formation of neurofibrillary changes. In addition, b-amyloid has
been shown to be toxic to neurons. 
In Alzheimer's Disease, b-Amyloid proteins derived from APP are the main component of
neuritic plaques. It is believed that errantly processed APP derivatives may induce
physiological processes that lead to neurodegeneration and plague formation. Many studies
have successfully linked APP with AD. One study on transgenic mice with human
APP717(associated with familial AD) displayed subcellular neurodegeneration similar to
those observed in AD, including dystrophic neurites, disruption of synaptic junction, and
intracellular amyloid and reactive gliosis. Amyloid deposits in the tg mice were very
similar to those found in AD and was readily recognized by anti-b-amyloid antibody. 
In other studies, Hippocampal pyramidal neurons in AD display an intense immunostaining
with 10 different antibodies against subsequences of APP. The area containing the stained
neurons were consistent with those showing the most neuropathology in AD. Collectively,
these data show APP as being closely associated with neurodegeneration. However, it is
still unclear if APP is the cause of cell death in the AD brain. APP could be one of many
factors participating with differnent intracellular processes to cause cell death. 
In hope of finding more information on Alzheimer's disease, researchers look for
similarities and connections to other more understood illnesses, one being the prion
disease. This disorder is a neurodegenerative disease characterized by prion protein
deposits and is associated with reactive astrocytes and microglial cells. Alzheimer's
disease is similarly characterized by plagues and inflammatory astrocytes. Many earlier
studies found that prion peptides and b-amyloid proteins activate microglial cells by
secreting cytokines, reactive oxygen species, and other neurotoxins. 
Analogous to typical inflammatory signaling response such as those mediated through
classical immune receptors, b-amyloid and prion proteins activate a common tyosine
kinase-dependent pathway. This was indicated by an elevated level of phosphotyrosine in
plaque associated microglials of AD. Microglial treated with inhibitors of specific
protein in the tyrosine kinase-based pathway successfully blocked amyloid-stimulated
secretion of neurotoxins and reduced the number of cell death. Despite this documentation
on amyloid-induced production of neurotoxins, it does not resolve the issue of what
causes AD. The species responsible for neurodegeneration in AD still remain
controversial. However, it does implicate b-amyloid peptide along with numerous
coordinated response pathways and mediating species.
Neurodegeneration in AD is suspected to be caused by apoptosis or programmed cell death.
Research with andenovirus-mediated APP gene transfer, demonstrate that neurons in vivo
are vulnerable to intracellular accumulation of APP. Hippocampal pyramidal neurons show
severe atrophy and nuclear DNA fragmentation, a typical feature of apoptosis. Infection
of rat hippocampal cells with an adonovirus contain APP695 cDNA enhanced glutamate
induced rise of intracellular Ca2+ concentration. Elevation of Ca2+ level in the cellular
compartment can cause activation of a numbers Ca2+-dependent degradative processes,
including apoptosis. Interestingly, one of the newly discovered apoptosis-linked genes
encodes a Ca2+ binding site. The increase in intracellular level of Ca2+ could come from
the impairment of glucose transporters. Data from studies in AD shows that the
transporters for Glucose uptake, GLUT3, to be decreased. When glucose uptake is
compromised, ATP production diminishes, Na/K+ pumps stops and the neuron depolarizes
releasing glutamate. Large release of glutamate can cause a Ca2+ overload in the neuron.
Thus, neurons with a compromised Ca2+ buffering system such as those found in the aging
or AD will be most affected by changes to Ca2+ level induced by b-Amyloid peptides.
In human neuronal cultures, application of physiological levels of Amyloid- b1-40 or
Amyloid- b1-42 produced no toxic effects. Interestingly, application of 100 nM rapidly
decreased bcl-2 protein levels(anti-apoptosis protein) in neurons and increased bax
levels(cell death promoting protein). Bcl-2 proteins is well established to be anti-death
proteins. They also showed that cells preexposed to the Amyloid-b proteins show increase
sensitivity to oxidative stress. Thus, Amyloid-b protein deposits per se do not cause
extensive apoptosis; They downregulate bcl-2 proteins and subsequently promote apoptosis
by rendering the neurons vulnerable to age-dependent secondary assaults. 
Secondary assaults on neurons such as oxidation has been shown to associate with
neuropathological lesions in Alzheimer's Disease. Thus, a proposed therapy for
neurodegeneration in AD is the use of antioxidants. Melatonin, a pineal hormone with
antioxidant properties, has been recently shown to effectively prevent death of
neuroblastoma cell induced by Amyloid-b. Melatonin also averted Amyloid-b-induced
increases in intracellular Ca2+ and lipid peroxidation. In correlation with AD, melatonin
has a physiological role in the aging process; Elderly individuals show a decreased
secretion of melatonin. The close association between aging and AD and the similarities
in neuropathology of both conditions suggest that decreasing level of melatonin in aging
individuals weakens the protective machinery of the neuron. Amyloid-b proteins may
participate in neurodegeneration by further compromising the already weaken defense
system of individuals at risk for AD.
It could be said that b-Amyloid peptides affect the neurons in AD opportunistically, by
taking advantage of an already weaken protective mechanism of the cell. The correlation
between the compromised neuron and secondary assaults is seen in the defect of
lysosomal/endosomal b-Amyloid removal machinery of the Aging and Alzheimer's. The
lysosomal/endosomal reuptake system is one of two pathways for the degradation of
secreted b-Amyloid proteins. The other pathway being degradation by extracellular
proteases. Infusion of b-Amyloid and leupeptin, a protease inhibitor, resulted in a
significant accumulation of b-Amyloid in the lysosomes. Lysosomal/endosomal compromise
related with age or Alzheimer's could cause an accumulation of Amyloid-b and mediate
neurotoxicity within the neuron.
b-Amyloid by itself does not seem to cause extensive problems in the brain; This peptide
is normally found in the cerebral spinal fluid of healthy individuals. The fact that
neurodegeneration occurs mainly around senile plaques and that neurotoxicity of this
peptide depends on its aggregation indicate that the fibrils are the initiating component
in AD. Thus, endogenous factors controlling fibrillogenesis and deposition could also
play a significant role in the pathogenesis of this disease. 
Acetylcholinesterase is one enzyme that can directly promotes the assembly of b-Amyloid
peptides into amyloid fibrils. Studies showed that incorporation of AchE into the
Alzheimer's amyloid aggregate resulted in the formation of a stable complex which changed
the biochemical and pharmacological properties of the enzyme, making the fibril more
neurotoxic. To further support AchE's relation to Alzheimer's disease, it was observed
that in more vulnerable areas of AD such as the entorhinal cortex, CA1 of the
hippocampus, and the amygdala, the AchE system is the first to be affected. Thus,
although b-Amyloid peptide is common factor in the pathogenesis of Alzheimer's disease,
it is by no mean the sole determinant of the disease progression. Interestingly, there
have been cases where amyloid plaques appear in the brain on non-demented individuals,
further proving that b-Amyloid does not invariably lead to AD. Other endogenous
contributing factors must be present in individuals at risk for AD.
An inherited form early onset of Alzheimer's Disease is known to be caused by mutations
in the PS-1 gene on Chromosome 14. Study of this gene confirm the belief that other
factors contribute to the neurotoxicity of b-Amyloid peptides. In cells over expressing
the mutant PS-1 L286V gene were extremely sensitive to apoptotic inducers. Data suggests
that the PS-1 gene affects regulate free radical metabolism and calcium homeostasis.
Thus, cells expressing the PS-1 mutation are under oxidative stress and are more
sensitive to an increase in b-Amyloid peptides.
It is uncertain whether b-Amyloid is the underlying cause of Alzheimer's Disease.
Exposure of this peptide to cultured neurons has been shown to cause extensive cellular
degeneration. Ironically, b-Amyloid can also be detected in healthy non-demented
subjects. It could be said that, in Alzheimer's Disease, b-Amyloid promote cellular
degeneration by working with many endogenous systems. Classical immune receptors, ion
homeostasis, anti-apoptotic proteins, anti-oxidants concentrations, lysosomal/endosomal
system, and AchE are a few key cellular systems that were mentioned in this review. In
individuals with a high risk for this disease, these systems are compromised in an unkown
fashion, thus, allowing b-Amyloid to assert a toxic effect on the neuron.