Intracellular APP Processing and Aβ Production in Alzheimer Disease

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Abstract
Senile plaques composed of Aβ peptides are a histopathological hallmark of Alzheimer disease (AD). A role for Aβ in the etiology of AD has been argued from analysis of mutations associated with a subset of early-onset familial AD (FAD). Expression of autosomal dominant mutations in the genes for the amyloid precursor protein (APP), prescnilin 1 (PS1), and prescnilin 2 (PS2) in affected patients, cultured cells, or transgenic mice leads to increased production of total Aβ or increased production of Aβ ending at residue 42(Aβ42). Since Aβ42 is the more amyloidogenic and toxic species in vitro and is the major component of amyloid senile plaques in vivo, overproduction of this peptide may play a crucial role in the pathogenesis of AD. Thus, an understanding of the production of Aβ within the cell in normal and pathological conditions is critical to understanding early events in AD. Studies in cell culture have established that processing of APP to form Ap can occur at multiple locations within the cell and leads to the production of 2 pools of Aβ: a secreted pool composed predominantly of Aβ40 and a nonsecreted, intracellular pool composed preferentially of more amyloidogenic Aβ42. The purpose of this review is to provide a summary of our current understanding of APP processing in the generation of the secreted and intracellular pools of Aβ and to propose a model linking the intracellular pool to the formation of extracellular plaques and neuronal pathology in AD.

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