Dysregulation of intracellular trafficking and endosomal sorting in Alzheimer's disease: controversies and unanswered questions.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques in the brain consisting of an aggregated form of amyloid β-peptide (Aβ) derived from sequential amyloidogenic processing of the amyloid precursor protein (APP) by membrane-bound proteases β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase. The initial processing of APP by BACE1 is re-gulated by intracellular sorting events of the enzyme, which is a prime target for therapeutic intervention. GWAS (genome-wide sequencing studies) have identified several AD-susceptibility genes that are associated with the regulation of membrane trafficking, and substantial evidence now indicates that AD is likely to arise from defective membrane trafficking in either or both of the secretory and endocytic pathways. Considerable progress has been made in defining the intracellular trafficking pathways of BACE1 and APP and the sorting signals of these membrane proteins that define their itineraries. In this review we highlight recent advances in understanding the regulation of the intracellular sorting of BACE1 and APP, discuss how dysregulation of these trafficking events may lead to enhanced generation of the neurotoxic Aβ products in AD and highlight the unresolved questions in the field.