Restoring Soluble Amyloid Precursor Protein α Functions as a Potential Treatment for Alzheimer's Disease

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More than 100 years have passed since Alois Alzheimer and Oskar Fisher's discovery of the two neuropathological hallmarks of Alzheimer's disease (AD), deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). Currently, AD is the most common type of age‐associated dementia, and there are no disease‐modifying treatments. The pathological features of AD are currently known to include 1) extracellular amyloid plaques composed largely of amyloid‐β (Aβ) peptides (Hardy and Allsop, 1991), 2) intracellular NFTs composed of the hyperphosphorylated microtubule‐associated protein tau (Goedert et al., 1991), 3) dysmorphic synapses, and 4) neuronal loss (Palop and Mucke, 2010). The proteolytic cleavage of amyloid precursor protein (APP) by two different enzymes, β (also called BACE1)‐ and γ‐secretases, is a critical step in AD development. In the nonamyloidogenic pathway, most of the APP is cleaved at the plasma membrane by α‐secretase, which precludes Aβ formation but produces a large secreted N‐terminal ectodomain of APP (sAPPα) of 105–125 kDa and small membrane‐bound α‐C‐terminal fragment (CTF; Haass and Selkoe, 1993). The membrane‐bound α‐CTF is cleaved by γ‐secretase complex, resulting in release of P3 peptide of 3 kDa and AICD (APP intracellular domain). In the amyloidogenic pathway, the remaining uncleaved APP is processed into the endosomal–lysosomal compartments by β‐secretase, resulting in soluble sAPPβ and membrane‐bound β‐CTF. The subsequent action of γ‐secretase on β‐CTF produces Aβ40/42 peptides and AICD (Kang et al., 1987). In addition to α‐, β‐, and γ‐secretases cleavage, a recent study identified that APP can be cleaved by the metalloprotease meprin β, generating soluble N‐terminally truncated APP (N‐APP) and N‐terminally truncated Aβ2‐X peptide variants, which show increased aggregation potential compared with nontruncated Aβ40 peptides (Jefferson et al., 2011; Bien et al., 2012; Schonherr et al., 2016). Cleavage of APP by meprin β occurs prior to the endocytosis, and different APP mutants affect the catalytic properties of the enzyme. More specifically, Swedish mutant APP does not undergo this cleavage and is unable to produce this truncated Aβ variants. Another study showed that APP can also be cleaved by matrix metalloproteinases such as MT5‐MMP, referred to as η‐secretase, which releases a long truncated ectodomain (sAPPη) and a membrane‐bound CTF, termed CTFη (Willem et al., 2015). The membrane‐bound CTFη is further cleaved by α‐ and β‐secretases, releasing both a long (Aη‐α) and a short (Aη‐β) peptide, respectively. The cleavage of η cuts far from the N‐terminus of the β‐secretase cleavage site and produces fragments (92 or 108 amino acids) that end at either the β‐ or the α‐secretase site, respectively (Willem et al., 2015; Fig. 1).
Several in vitro and in vivo studies have demonstrated the toxic properties of Aβ peptides since the first identification of the APP gene in 1987 (Kang et al., 1987; Younkin, 1995). Administration of Aβ peptides (Maurice et al., 1996), their structural mimetics, and anti‐Aβ antibodies (Cleary et al., 1995) have supported the deleterious functions of the peptide in terms of promoting cognitive deficits. Like sAPPα, sAPPβ has beneficial effects, is soluble in nature, and is secreted extracellularly but lacks 16 amino acids at the C‐terminus. The potency of sAPPβ is found to be 100 times less than that of sAPPα, measured by its ability to protect hippocampal neurons from excitotoxicity, glucose deprivation, and Aβ toxicity (Furukawa et al., 1996b; Barger and Harmon, 1997). In accordance with this finding, other studies also reported the reduced potency of sAPPβ as a neuroprotective fragment (Li et al., 1997; Turner et al., 2003). Like sAPPα, sAPPβ also supports axonal outgrowth (Chasseigneaux et al., 2011) and neural differentiation of human embryonic stem cells (Freude et al., 2011).

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