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  • As with the GSIs there are again major

    2022-05-16

    As with the GSIs, there are again major concerns that GSM therapy in patients with symptomatic AD is almost certain to fail, unless the compound has additional mechanism of action not linked to Aβ that prove to beneficial [52]. Although Aβ1–42 or other longer Aβ peptides are critical for initiating Aβ deposition, shorter Aβ accumulate in the AD brain [189]. Thus, shifting Aβ cleavage after nucleation events have occurred is not likely to dramatically alter Aβ deposition kinetics. Thus, a major challenge is whether a sufficiently safe GSM can be developed that can potentially be used as a prophylactic agent in asymptomatic individuals. A final issue of clinical relevance relates to the biology of the shorter Aβ peptides. There has been little systematic investigation of these peptides. Although one report suggested that Aβ1–38 may behave in vitro like Aβ1–42, this important finding has not been reproduced [190]. Further study of these short peptides may reveal unique properties that might help to guide development of GSMs. For example Aβ1–40 appears to act an inhibitor of Aβ1–42 nucleation and aggregation in vivo[191], [192], but whether Aβ1–37 or 1–38 inhibit aggregation in vivo is unknown. Given that non-acidic GSMs decrease Aβ1–40 whereas acidic GSMs do not, the distinct action of these two classes of GSMs could have major impact on efficacy.
    Conclusions
    Acknowledgements
    Background Alzheimer’s disease (AD) is a global health crisis. It is a neurodegenerative disorder characterized by amyloid plaques made of amyloid beta WAY-600 (Aβ) and neurofibrillary tangles (NFT) made of hyper-phosphorylated tau protein. Symptoms include memory loss and behavioral deficits (Musiek and Holtzman, 2015), and there is no cure for this disease. This is especially troubling as the number one risk factor for AD is age, and the western world has an aging population. While NFT align more closely with disease stage (Arriagada et al., 1992, Giannakopoulos et al., 2003), researchers believe amyloid beta (Aβ) to be causative in the disorder, mainly because of the genetic evidence (Musiek and Holtzman, 2015). Autosomal dominant AD is caused by mutations in amyloid precursor protein (APP) or presenilin, the catalytic subunit of gamma-secretase (GS) (Ahn et al., 2010, Bettens et al., 2013), and these mutations lead to an increase in Aβ and downstream dementia. Amyloid precursor protein (APP) can be cleaved by two pathways, the non-amyloidogenic versus the amyloidogenic pathway (Zheng and Koo, 2011). In the non-amyloidogenic pathway, APP is first cleaved by alpha-secretase and then by GS. In the amyloidogenic pathway, however, the first cleavage is done by beta-secretase (BACE) then. This second pathway releases Aβ of varying lengths (Fig. 1), with GS first cleaving the β-CTF into long forms of Aβ, either Aβ48 or Aβ49. GS then makes step-wise cleavages every three amino acids, preferring Aβ40 and Aβ42 (Barnwell et al., 2014, Li et al., 2016, Qi-Takahara et al., 2005, Takami et al., 2009). Aβ42 production may also not relate solely to the cleavage of the longer Aβ forms, but instead may depend on the dissociation rate of Aβ42 from the complex. If it remains in the active site, it may cleave further into shorter forms (Okochi et al., 2013). APP cleavage is a more complicated process than was originally described. Of the Aβ lengths, Aβ42 is believed to be more toxic then Aβ40. Scientists measure the ratio of Aβ42: Aβ40, and when this ratio increases, like in genetic forms of AD, Aβ peptides oligomerize more readily (Iwatsubo et al., 1994). After oligomerization, the Aβ species then aggregate, eventually leading to downstream neurotoxicity. The original hypothesis for AD, the Aβ hypothesis coined by Hardy and Higgins (Hardy and Selkoe, 2002, Hardy and Higgins, 1992) has been updated to place Aβ not as the sole instigator of a direct cascade, but instead as an initiator for a series of changes, many through tau protein and inflammation, that eventually lead to neurodegeneration (Musiek and Holtzman, 2015).