Amyloid precursor protein trafficking, processing, and function

Abstract

Intracellular trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations over the past two decades. APP is the precursor to the amyloid beta-protein (Abeta), the 38-43-amino acid residue peptide that is at the heart of the amyloid cascade hypothesis of Alzheimer disease (AD). Tremendous progress has been made since the initial identification of Abeta as the principal component of brain senile plaques of individuals with AD. Specifically, molecular characterization of the secretases involved in Abeta production has facilitated cell biological investigations on APP processing and advanced efforts to model AD pathogenesis in animal models. This minireview summarizes salient features of APP trafficking and amyloidogenic processing and discusses the putative biological functions of APP.

FIGURE 1.

Proteolytic processing of APP. A, the schematic structure of APP is shown with the Aβ domain shaded in red and enlarged. The major sites of cleavage by α-, β-, and γ-secretases are indicated along with Aβ numbering from the N terminus of Aβ (Asp¹). B, non-amyloidogenic processing of APP refers to sequential processing of APP by membrane-bound α- and γ-secretases. α-Secretase cleaves within the Aβ domain, thus precluding generation of intact Aβ peptide. The fates of N-terminally truncated Aβ (p3) and AICD are not fully resolved. C, amyloidogenic processing of APP is carried out by sequential action of membrane-bound β- and γ-secretases. CTF, C-terminal fragment.

FIGURE 2.

Intracellular trafficking of APP. Nascent APP molecules (black bars) mature through the constitutive secretory pathway (step 1). Once APP reaches the cell surface, it is rapidly internalized (step 2) and subsequently trafficked through endocytic and recycling compartments back to the cell surface (step 3) or degraded in the lysosome. Non-amyloidogenic processing occurs mainly at the cell surface, where α-secretases are present. Amyloidogenic processing involves transit through the endocytic organelles, where APP encounters β- and γ-secretases.