Localization and Trafficking of Amyloid-β Protein Precursor and Secretases: Impact on Alzheimer's Disease

Alzheimer's disease (AD) affects almost 35 million people worldwide. One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-beta (A beta) peptides. These peptides derive from the amyloidogenic proteolytic processing of the amyloid-beta protein precursor (A beta PP), through the sequential action of beta-and gamma-secretases. However, A beta PP can also be cleaved by a non-amyloidogenic pathway, involving an alpha-secretase, and in this case the A beta formation is precluded. The production of A beta and of other A beta PP catabolites depends on the spatial and temporal co-localization of A beta PP with alpha- or beta-secretases and gamma-secretase, which traffic through the secretory pathway in a highly regulated manner. Disturbances on A beta PP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. In this article, we critically review the recent knowledge about the trafficking and co-localization of A beta PP and related secretases in the brain under physiological and AD conditions. A particular focus is given to data concerning the distribution of A beta PP and secretases in different types of synapses relatively to other neuronal or glial localizations. Furthermore, we discuss some possible signals that govern the dynamic encounter of A beta PP with each group of secretases, such as A beta PP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. The knowledge of key signals that are responsible for the shifting of A beta PP processing away from alpha-secretases and toward the beta-secretases might be useful to develop AD therapeutic strategies.