Alzheimers disease (AD) is a common neurodegenerative disease that affects cognitive function in the elderly. Large extracellular beta-amyloid (Aβ) plaques and tau-containing intraneuronal neurofibrillary tangles characterize AD from a histopathologic perspective. However, the severity of dementia in AD is more closely related to the degree of the associated neuronal and synaptic loss. It is not known how neurons die and synapses are lost in AD the current review summarizes what is known about this issue. Most evidence indicates that amyloid precursor protein (APP) processing is central to the AD process. The Aβ in plaques is a metabolite of the APP that forms when an alternative (beta-secretase and then gamma-secretase) enzymatic pathway is utilized for processing. Mutations of the APP gene lead to AD by influencing APP metabolism. One leading theory is that the Aβ in plaques leads to AD because Aβ is directly toxic to the adjacent neurons. Other theories advance the notion tha t neuronal death is triggered by intracellular events that occur during APP processing or by extraneuronal preplaque Aβ oligomers. Some investigators speculate that in many cases there is a more general disorder of protein processing in neurons that leads to cell death. In the later models, Aβ plaques are a byproduct of the disease process, rather than the direct cause of neuronal death. A direct correlation between Aβ plaque burden and neuronal (or synaptic) loss should occur in AD if Aβ plaques cause AD through a direct toxic effect. However, histopathologic studies indicate that the correlation between Aβ plaque burden and neuronal (or synaptic) loss is poor. We conclude that APP processing and Aβ formation is important to the AD process, but that neuronal alterations that underlie symptoms of AD are not due exclusively to a direct toxic effect of the Aβ deposits that occur in plaques. A more general problem with protein processing, damage due to the neuron from accumulat ion of intraneuronal Aβ or extracellular, preplaque Aβ may also be important as underlying factors in the dementia of AD.
Keywords: Amyloid, Neuronal Death, dementia, neurotoxicity
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