Alzheimer's disease and amyloid: culprit or coincidence?

Stephen D Skaper
International Review of Neurobiology 2012, 102: 277-316
Alzheimer's disease (AD) is the largest unmet medical need in neurology today. This most common form of irreversible dementia is placing a considerable and increasing burden on patients, caregivers, and society, as more people live long enough to become affected. Current drugs improve symptoms but do not have profound neuroprotective and/or disease-modifying effects. AD is characterized by loss of neurons, dystrophic neurites, senile/amyloid/neuritic plaques, neurofibrillary tangles, and synaptic loss. Beta-amyloid (Aβ) peptide deposition is the major pathological feature of AD. Increasing evidence suggests that overexpression of the amyloid precursor protein and subsequent generation of the 39-43 amino acid residue, Aβ, are central to neuronal degeneration observed in AD patients possessing familial AD mutations, while transgenic mice overexpressing amyloid precursor protein develop AD-like pathology. Despite the genetic and cell biological evidence that supports the amyloid hypothesis, it is becoming increasing clear that AD etiology is complex and that Aβ alone is unable to account for all aspects of AD. The fact that vast overproduction of Aβ peptides in the brain of transgenic mouse models fails to cause overt neurodegeneration raises the question as to whether accumulation of Aβ peptides is indeed the culprit for neurodegeneration in AD. There is increasing evidence to suggest that Aβ/amyloid-independent factors, including the actions of AD-related genes (microtubule-associated protein tau, polymorphisms of apolipoprotein E4), inflammation, and oxidative stress, also contribute to AD pathogenesis. This chapter reviews the current state of knowledge on these factors and their possible interactions, as well as their potential for neuroprotection targets.

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