Alzheimer`s DiseaseAlzheimer’s Disease is a progressive, degenerative disease that affects thebrain.
Individuals with AD experience a progressive and specific loss ofcognitive function resulting from the differentiation of the limbic system,association neocortex, and basal forebrain. It is also accompanied by thedeposition of amyloid in plaques and cerebrovasculature, and the formation ofneurofibrillary tangles in neurons. Alois Alzheimer, a German doctor, diagnosedthis disease for the first time in 1907. At that time it was considered a raredisorder.
Currently, this tragic brain disorder affects approximately fourmillion people; It is the most common type of dementia and the fourth leadingcause of death in the United States. Many studies have been done and are stillbeing conducted to determine the exact cause of AD. The molecular and biologicalbasis for the degeneration of neurons in AD is incompletely understood. However,the APP(Amyloid Precursor Protein) and its proteolytic fragments have beenimplicated more often than not and is the focus of most current studies. Severallines of evidence have strengthened the amyloid hypothesis for Alzheimer’sDisease.
The first being the identification of point mutations with the APP genein groups of patients afflicted with the familial forms of AD. Second, amyloiddeposition temporally precedes the formation of neurofibrillary changes. Inaddition, b-amyloid has been shown to be toxic to neurons. In Alzheimer’sDisease, b-Amyloid proteins derived from APP are the main component of neuriticplaques. It is believed that errantly processed APP derivatives may inducephysiological processes that lead to neurodegeneration and plague formation.
Many studies have successfully linked APP with AD. One study on transgenic micewith human APP717(associated with familial AD) displayed subcellularneurodegeneration 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 wasreadily recognized by anti-b-amyloid antibody. In other studies, Hippocampalpyramidal neurons in AD display an intense immunostaining with 10 differentantibodies against subsequences of APP. The area containing the stained neuronswere 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 couldbe one of many factors participating with differnent intracellular processes tocause cell death. In hope of finding more information on Alzheimer’s disease,researchers look for similarities and connections to other more understoodillnesses, one being the prion disease. This disorder is a neurodegenerativedisease characterized by prion protein deposits and is associated with reactiveastrocytes and microglial cells.
Alzheimer’s disease is similarlycharacterized by plagues and inflammatory astrocytes. Many earlier studies foundthat prion peptides and b-amyloid proteins activate microglial cells bysecreting cytokines, reactive oxygen species, and other neurotoxins. Analogousto typical inflammatory signaling response such as those mediated throughclassical immune receptors, b-amyloid and prion proteins activate a commontyosine kinase-dependent pathway. This was indicated by an elevated level ofphosphotyrosine in plaque associated microglials of AD. Microglial treated withinhibitors of specific protein in the tyrosine kinase-based pathway successfullyblocked amyloid-stimulated secretion of neurotoxins and reduced the number ofcell death. Despite this documentation on amyloid-induced production ofneurotoxins, it does not resolve the issue of what causes AD.
The speciesresponsible for neurodegeneration in AD still remain controversial. However, itdoes implicate b-amyloid peptide along with numerous coordinated responsepathways and mediating species. Neurodegeneration in AD is suspected to becaused by apoptosis or programmed cell death. Research with andenovirus-mediatedAPP gene transfer, demonstrate that neurons in vivo are vulnerable tointracellular accumulation of APP. Hippocampal pyramidal neurons show severeatrophy and nuclear DNA fragmentation, a typical feature of apoptosis. Infectionof rat hippocampal cells with an adonovirus contain APP695 cDNA enhancedglutamate induced rise of intracellular Ca2+ concentration.
Elevation of Ca2+level in the cellular compartment can cause activation of a numbersCa2+-dependent degradative processes, including apoptosis. Interestingly, one ofthe newly discovered “apoptosis-linked genes” encodes a Ca2+ bindingsite. The increase in intracellular level of Ca2+ could come from the impairmentof glucose transporters. Data from studies in AD shows that the transporters forGlucose uptake, GLUT3, to be decreased.
When glucose uptake is compromised, ATPproduction diminishes, Na/K+ pumps stops and the neuron depolarizes releasingglutamate. Large release of glutamate can cause a Ca2+ overload in the neuron. Thus, neurons with a compromised Ca2+ buffering system such as those found inthe aging or AD will be most affected by changes to Ca2+ level induced by b-Amyloidpeptides. In human neuronal cultures, application of physiological levels ofAmyloid- b1-40 or Amyloid- b1-42 produced no toxic effects. Interestingly,application of 100 nM rapidly decreased bcl-2 protein levels(anti-apoptosisprotein) in neurons and increased bax levels(cell death promoting protein).
Bcl-2 proteins is well established to be anti-death proteins. They also showedthat cells preexposed to the Amyloid-b proteins show increase sensitivity tooxidative stress. Thus, Amyloid-b protein deposits per se do not cause extensiveapoptosis; They downregulate bcl-2 proteins and subsequently promote apoptosisby rendering the neurons vulnerable to age-dependent secondary assaults. Secondary assaults on neurons such as oxidation has been shown to associate withneuropathological lesions in Alzheimer’s Disease. Thus, a proposed therapy forneurodegeneration in AD is the use of antioxidants. Melatonin, a pineal hormonewith antioxidant properties, has been recently shown to effectively preventdeath of neuroblastoma cell induced by Amyloid-b.
Melatonin also averted Amyloid-b-inducedincreases in intracellular Ca2+ and lipid peroxidation. In correlation with AD,melatonin has a physiological role in the aging process; Elderly individualsshow a decreased secretion of melatonin. The close association between aging andAD and the similarities in neuropathology of both conditions suggest thatdecreasing level of melatonin in aging individuals weakens the protectivemachinery of the neuron. Amyloid-b proteins may participate in neurodegenerationby further compromising the already weaken defense system of individuals at riskfor AD.
It could be said that b-Amyloid peptides affect the neurons in ADopportunistically, by taking advantage of an already weaken protective mechanismof the cell. The correlation between the compromised neuron and secondaryassaults is seen in the defect of lysosomal/endosomal b-Amyloid removalmachinery of the Aging and Alzheimer’s. The lysosomal/endosomal reuptakesystem is one of two pathways for the degradation of secreted b-Amyloidproteins. The other pathway being degradation by extracellular proteases.
Infusion of b-Amyloid and leupeptin, a protease inhibitor, resulted in asignificant accumulation of b-Amyloid in the lysosomes. Lysosomal/endosomalcompromise related with age or Alzheimer’s could cause an accumulation ofAmyloid-b and mediate neurotoxicity within the neuron. b-Amyloid by itself doesnot seem to cause extensive problems in the brain; This peptide is normallyfound in the cerebral spinal fluid of healthy individuals. The fact thatneurodegeneration occurs mainly around senile plaques and that neurotoxicity ofthis peptide depends on its aggregation indicate that the fibrils are theinitiating component in AD. Thus, endogenous factors controlling fibrillogenesisand deposition could also play a significant role in the pathogenesis of thisdisease. Acetylcholinesterase is one enzyme that can directly promotes theassembly of b-Amyloid peptides into amyloid fibrils.
Studies showed thatincorporation of AchE into the Alzheimer’s amyloid aggregate resulted in theformation of a stable complex which changed the biochemical and pharmacologicalproperties of the enzyme, making the fibril more neurotoxic. To further supportAchE’s relation to Alzheimer’s disease, it was observed that in morevulnerable 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-Amyloidpeptide is common factor in the pathogenesis of Alzheimer’s disease, it is byno mean the sole determinant of the disease progression. Interestingly, therehave been cases where amyloid plaques appear in the brain on non-dementedindividuals, further proving that b-Amyloid does not invariably lead to AD. Other endogenous contributing factors must be present in individuals at risk forAD. An inherited form early onset of Alzheimer’s Disease is known to be causedby mutations in the PS-1 gene on Chromosome 14.
Study of this gene confirm thebelief that other factors contribute to the neurotoxicity of b-Amyloid peptides. In cells over expressing the mutant PS-1 L286V gene were extremely sensitive toapoptotic inducers. Data suggests that the PS-1 gene affects regulate freeradical metabolism and calcium homeostasis. Thus, cells expressing the PS-1mutation are under oxidative stress and are more sensitive to an increase in b-Amyloidpeptides. It is uncertain whether b-Amyloid is the underlying cause ofAlzheimer’s Disease.
Exposure of this peptide to cultured neurons has beenshown to cause extensive cellular degeneration. Ironically, b-Amyloid can alsobe detected in healthy non-demented subjects. It could be said that, inAlzheimer’s Disease, b-Amyloid promote cellular degeneration by working withmany endogenous systems. Classical immune receptors, ion homeostasis,anti-apoptotic proteins, anti-oxidants concentrations, lysosomal/endosomalsystem, and AchE are a few key cellular systems that were mentioned in thisreview. In individuals with a high risk for this disease, these systems arecompromised in an unkown fashion, thus, allowing b-Amyloid to assert a toxiceffect on the neuron.
