Amyloid β production along the neuronal secretory pathway: Dangerous liaisons in the Golgi?

beta-amyloid peptides (A beta) are generated in intracellular compartments of neurons and secreted to form cytotoxic fibrils and plaques. Dysfunctional membrane trafficking contributes to aberrant A beta production and Alzheimer's disease. Endosomes represent one of the major sites for A beta production and recently the Golgi has re-emerged also as a major location for amyloid precursor protein (APP) processing and A beta production. Based on recent findings, here we propose that APP processing in the Golgi is finely tuned by segregating newly-synthesised APP and the beta-secretase BACE1 within the Golgi and into distinct trans-Golgi network transport pathways. We hypothesise that there are multiple mechanisms responsible for segregating APP and BACE1 during transit through the Golgi, and that perturbation in Golgi morphology associated with Alzheimer's disease, and or changes in cholesterol metabolism associated with Alzheimer's disease risk factors, may lead to a loss of partitioning and enhanced A beta production.

Automated summary

Recent studies have shown that endosomes and the Golgi are major sites for Aβ production. The processing of APP in the Golgi is finely controlled by segregating newly-synthesised APP and the beta-secretase BACE1 through distinct transport pathways. Dysfunction in Golgi morphology and cholesterol metabolism associated with Alzheimer's disease may lead to increased Aβ production.