The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

Abstract

The amyloid precursor protein (APP) has occupied a central position in Alzheimer’s disease (AD) pathophysiology, in large part due to the seminal role of amyloid-β peptide (Aβ), a proteolytic fragment derived from APP. Although the contribution of Aβ to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP’s involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPβ), various C- and N-terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the –YENPTY– motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.

APP mouse models for Alzheimer's disease preclinical studies

“…Overproduced non‐Aβ APP fragments may interact unphysiologically with cellular proteins (Chang & Suh, 2005; Mitani et al , 2012; Nicolas & Hassan, 2014; Kerridge et al , 2015; Nhan et al , 2015; Willem et al , 2015; Xia et al , 2016). See Fig 3.…”

Altered neurogenesis in mouse models of Alzheimer disease

“…APP can undergo a variety of different cleavage steps executed by certain secretases, which can be roughly subdivided into amyloidogenic and non-amyloidogenic processing (reviewed in ref. 13). In the amyloidogenic processing pathway, APP is initially cleaved by b-secretase, leading to the liberation of a long soluble extracellular fragment (sAPPb) and a membrane-bound C-terminal stub (b-CTF or C99), containing the Ab sequence.…”

“…Alternatively, initial cleavage by a-secretase within the Ab domain precludes Ab peptide generation by releasing a slightly shorter soluble APP fragment (sAPPa). Following g-secretase cleavage again releases the AICD fragment, as well as another small peptide named p3 with so far unknown function 13 (Fig. 1A).…”

New tricks from an old dog: Another synaptotoxic fragment from APP

“…Subsequent cleavage by γ-secretase generates Aβ peptide that is believed to play a seminal role in AD pathogenesis [2]. In this report, Willem and colleagues investigated APP fragments at approximately 25kDa that ends at the APP C-terminus [1].…”

“…While Aβ peptide has been shown to be neurotoxic, the N-terminal portion, i.e. within 1-16 of the Aβ sequence, was reported to exhibit neurotrophic effects [2]. Indeed, earlier studies have argued that the trophic properties of sAPP are in part attributable to this same region, possibly because the -RHDS-motif at positions 5-8 exhibits cell adhesion properties in an integrin-like manner [7,8].…”