Alzheimer`s Disease Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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. Alzheimers 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 Alzheimers 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 Alzheimers.
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 Alzheimers 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 Alzheimers 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 AchEs relation to Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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.