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  • Acknowledgements br Introduction Alzheimer s disease AD

    2021-11-25

    Acknowledgements
    Introduction Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia. There is currently no treatment available to slow or halt disease progression. The underlying mechanisms of AD on the cell and molecular levels are still not completely elucidated. Considerable genetic, pathological, biochemical, and molecular biological evidence supports the amyloid-cascade hypothesis, stating that the production and excessive accumulation of a small peptide, amyloid-β (Aβ), is the primary pathological event leading to AD (Gandy, 2005; Hardy and Selkoe, 2002; Tanzi and Bertram, 2005). Specifically, the accumulation of Aβ, particularly the neurotoxic Aβ42 peptide, affects neuronal synaptic functions and triggers an inflammatory response which is followed by neuritic injury and the generation of pathological tau proteins, ultimately leading to neuronal dysfunction and cell death. AD is a genetically complex disease. Four AD CU CPT 4a (APP, PSEN1, PSEN2 and APOE) have been identified which primarily serve to increase the ratio of Aβ42 to Aβ40 or in the case of the Swedish mutation, absolute Aβ peptide levels. The imbalance triggered by these genetic aberrations enhances the oligomerization of Aβ into neurotoxic assemblies and ultimately leads to dementia (Bertram and Tanzi, 2008; Choi et al., 2014; Tanzi and Bertram, 2005). In the amyloidogenic pathway, Aβ is produced via sequential proteolytic cleavage of the type I transmembrane protein, amyloid-β (A4) precursor protein (APP) by β- and γ-secretase, respectively (Bertram and Tanzi, 2008; Zhang and Saunders, 2007). γ-Secretase is a heterogeneous protein complex, formed by at least four transmembrane proteins: presenilin (PS1), presenilin enhancer 2 (PEN2), nicastrin, and anterior pharynx-defective 1(APH-1) (Bertram and Tanzi, 2008; Edbauer et al., 2003; Sisodia and St George-Hyslop, 2002). Over 200 mutations in the PS1-encoding gene (PSEN1) have been identified to cause early-onset familial AD (EOFAD), underscoring the relevance of the enzyme with respect to the disease. γ-Secretase regulates the intramembrane proteolysis of APP and numerous other substrates that have previously undergone ectodomain shedding, including Notch (Gu et al., 2004; Kopan and Ilagan, 2004; Sisodia and St George-Hyslop, 2002). The processing of Notch at the ε-site (or s3) represents a critical function of γ-secretase which yields a large cytoplasmic peptide, the Notch intracellular domain (NICD), which can translocate to the nucleus and is essential for cellular differentiation and development (Herreman et al., 1999; Kopan et al., 1994). One essential strategy for AD therapeutics has focused specifically on APP processing and attenuating Aβ production (Bertram and Tanzi, 2008; Selkoe, 2001; Zhang, 2012, Zhang, 2017). Initially, a class of drugs known as γ-secretase inhibitors (GSIs), were developed which potently inhibit γ-secretase activity. Despite the ability to preclude Aβ production, GSIs exhibit unfavorable activities that result in cell toxicity through increasing the levels of APP carboxy-terminal fragments (CTFs; CTFα and CTFβ), and side effects potentially elicited through down-regulation of Notch processing (Mitani et al., 2012). One of the well-characterized GSIs is semagacestat (or LY450139) (Doody et al., 2013; Mitani et al., 2012). Although it decreased the levels of all Aβ species (Potter et al., 2013), semagacestat recently failed in the pivotal phase 3 clinical trial for AD (Doody et al., 2013). Nevertheless, the results provide useful knowledge toward the features of a therapeutic for AD, which should avoid unfavorable adverse events associated with inhibition strategies in targeting either γ-, or β-secretease (De Strooper, 2014; Ward et al., 2017; Willem et al., 2015). Furthermore, this result provides evidence for a general need of improved understanding with respect to the critical biological roles of γ-secretase especially within the context of therapeutic development (De Strooper, 2014; Zhang, 2017).