Molecular and Cellular Mechanisms for Alzheimer's Disease:Understanding APP Metabolism

Alzheimer's disease (AD) is the most common neurodegenerative disease associated with aging. One important pathologic feature of AD is the formation of extracellular senile plaques in the brain, whose major components are small peptides called β-amyloid (Aβ) that are derived from β-amyloid precursor protein (APP) through sequential cleavages by β-secretase and γ-secretase. Because of the critical role of Aβ in the pathogenesis of AD, unraveling the cellular and molecular events underlying APP/Aβ metabolism has been and remains, of paramount importance to AD research. In this article we will focus on the regulation of APP metabolism leading to Aβ generation. We will review current knowledge of the secretases (α-, β-, and γ- secretases) involved in APP processing and various molecular and cellular mechanisms underlying intracellular trafficking of APP, which is a highly regulated process and whose disturbance has direct impacts on the production of Aβ.