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.