Physiological functions of APP family proteins

Abstract

Biochemical and genetic evidence establishes a central role of the amyloid precursor protein (APP) in Alzheimer disease (AD) pathogenesis. Biochemically, deposition of the β-amyloid (Aβ) peptides produced from proteolytic processing of APP forms the defining pathological hallmark of AD; genetically, both point mutations and duplications of wild-type APP are linked to a subset of early onset of familial AD (FAD) and cerebral amyloid angiopathy. As such, the biological functions of APP and its processing products have been the subject of intense investigation, and the past 20+ years of research have met with both excitement and challenges. This article will review the current understanding of the physiological functions of APP in the context of APP family members.

Figure 1.

Schematic overview of domain structure of APP family proteins. All APP family members share conserved E1 and E2 extracellular domains, an acidic domain (Ac) and the YENPTY motif in the carboxyl terminus. Note that Aβ is unique for APP. HBD, Heparin binding domain; CuBD, Copper binding domain; KPI, Kunitz-type protease inhibitor domain.

Figure 2.

Schematic representation of APP and its knock-in constructs (not drawn to scale). EX, TM, and IC stand for extracellular, transmembrane, and intracellular region, respectively. E1 and E2 domains are marked in yellow and orange, respectively. mAβ and hAβ represent mouse and human Aβ, respectively. β, α, and γ indicate the cleavage sites by β-, α-, and γ-secretase, respectively. *** represents signal peptide. *** symbolizes the FLAG tag. Residue T⁶⁶⁸, and YENPTY motif are labeled to illustrate the corresponding point mutations in APP-YG knock-in and APP-TA knock-in mice. *, Swedish mutation (K595M596-N595L596); **, Arctic mutation (E618-G618); ***, London mutation (V642-I618), which are introduced in the APP/hAβ/mutC knock-in allele. All residues are numbered according to APP695 numbering.