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.

Fig. 1

APP processing and cleavage products. a The right-hand panel illustrates the non-amyloidogenic APP processing pathway, which is initiated by α-secretase cleavage, whereas the left-hand panel depicts the amyloidogenic processing pathway as initiated by β-secretase cleavage. Both secretase-mediated cleavage events generate soluble ectodomains of APP (sAPPα and sAPPβ) and two membrane-tethered C-terminal fragments (CTFα and CTFβ, also known as C83 and C99). Subsequent cleavage within the transmembrane domain by γ-secretase yields the 3-kDa peptide p3 and the 4-kDa Aβ, respectively, along with the release of the cytoplasmic polypeptide termed AICD. The amino acid sequences (with numbering based on the APP695 isoform) are shown for three domains of significance: (1) the Aβ_1–42 sequence that begins with D¹ and ends with A⁴²; (2) the VEVD₆₆₄ sequence, which is a putative caspase cleavage motif; and (3) the Y₆₈₂ENPTY₆₈₇ sequence, which is a clathrin-mediated endocytosis motif that has been shown to modulate several APP functions through phosphorylation and dephosphorylation of the first tyrosine residue. The physiological functions of APP and its cleavage products have been classified as primarily beneficial, detrimental, or ambiguous depending on our judgment of where the weight of the evidence lies; this is meant only as a rough introduction to these multifunctional peptides. For example, we have categorized sAPPα as beneficial, as it is largely associated with trophic effects, although it should be noted that over-expression can lead to a tumorigenic phenotype. b APP processing can also proceed down a non-canonical pathway, where it is thought that caspase cleavage after VEVD₆₆₄ results in additional fragments, including Jcasp (from the N-terminus of AICD to D₆₆₄) and C31 (from the caspase cleavage site to the C-terminus of APP), along with various APP and CTFs lacking the last 31 amino acids

Fig. 2

Caspase-mediated APP cleavage generates the neurotoxic C31 species. A proposed model of C31 generation is presented here, wherein Aβ binding promotes APP dimerization, resulting in caspase cleavage after D₆₆₄ and generation of the C31 peptide. C31 has been shown to cause synaptic dysfunction and neuronal death, effects which are mitigated by alanine substitution at residue D₆₆₄, presumably due to abrogated caspase cleavage and consequent blockage of C31 production

Fig. 3

AICD and the YENPTY domain of APP. γ-secretase cleavage of APP generates AICD, typically a highly unstable molecule, although binding to Fe65 family members results in its stabilization and translocation to the nucleus. This complex, in association with CP2/LSF/LBP and Tip60, has been shown to transactivate GSK-3β, with kinase upregulation leading to tau hyperphosphorylation, which can be inhibited by lithium chloride treatment. Proteins containing phosphotyrosine-binding (PTB) domains, such as the Fe65 family members, bind to APP when Y₆₈₂ is dephosphorylated, but their binding is inhibited when Y₆₈₂ is phosphorylated (as shown in the right-hand inset box, going counterclockwise), which conversely promotes the binding of SH2 domain-containing proteins like Shc, Grb2/7, and Src. Phosphorylation of T₆₆₈ in addition to Y₆₈₂ promotes binding of the Pin1 isomerase and further potentiates binding by SH2 domain proteins, while phosphorylation of only the T₆₆₈ residue inhibits this interaction