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    • a little of br Conclusions Our study confirms that N termina

    2023-01-30


    Conclusions Our study confirms that N-terminal mutations can affect Aβ fibril and oligomer formation, despite lying outside the core amyloid region of Aβ. Of the three factors that may influence Aβ-mediated toxicity (primary structure of Aβ, assembly structure and cellular responses), our results suggest that it is more the assembly structure that correlates with effects on cell viability. N-terminal mutations produced three peptides, all with reduced propensity to form fibrils, increased oligomer size distributions, and reduced toxicities. Because the mutant oligomers formed were larger and less toxic but unable to rescue the damaging effects of hAβ1–42 oligomers, we conclude that larger assembly size and/or alteration of N-terminal a little of prevented interaction with the cell membrane and binding receptors required to induce toxicity. Whether distinct cell types (e.g., neurons, glia or non-neuronal cells) would respond differently to these Aβ assemblies was beyond the scope of this study, but if the N-terminus of Aβ can be targeted such that oligomer size is increased, that may be sufficient to block downstream effects on cell viability.
    Disclosure statement
    Author contributions
    Acknowledgments This work was supported by a grant from the Alberta Prion Research Institute (APRI)/Alzheimer’s Society of Alberta and the Northwest Territories (ASANT) to SK (AIBS AARP 201300016) and VLS (AIBS AARP 201600002).
    Introduction Epidemiological studies have demonstrated that depression may be a risk factor for Alzheimer's disease (AD) (Devanand et al., 1996, Wilson et al., 2002, Ownby et al., 2006, Irie et al., 2008, Byers and Yaffe, 2011, Barnes et al., 2012, da Silva et al., 2013, Diniz et al., 2013). This association has been shown even in cases where depression occurs long before the onset of AD (Green et al., 2003, Ownby et al., 2006). Recent studies have supported the idea that early-onset depression also increases the risk of developing AD (Geerlings et al., 2008, Byers and Yaffe, 2011, da Silva et al., 2013). Moreover, the number of depressive episodes (Kessing and Andersen, 2004, Dotson et al., 2010) and severity of depressive symptoms (Wilson et al., 2002, Saczynski et a little of al., 2010) may increase the risk of dementia including AD. Whether depression is a prodromal symptom of AD or risk factor that contributes to its onset is still debated, although previous reports suggest the latter. Although the biological mechanism underlying the transition from depression to AD is still not clear, alterations of amyloid β protein (Aβ) metabolism in depression may be the possible background (Kita et al., 2009, Byers and Yaffe, 2011, Baba et al., 2012, Namekawa et al., 2013). Aβ is the major component of senile plaques in AD and is a 40- or 42-amino acid peptide cleaved from the amyloid precursor protein (APP) by β- and γ-secretase. Cerebrospinal fluid (CSF) levels of Aβ42 are reduced in patients with AD (Schroder et al., 1997, Andreasen et al., 1999), but increase at the early stage of the disease (Jensen et al., 1999). These variations may be associated with the selective deposition of Aβ42 in the brain. However, studies of plasma Aβ levels in subjects with AD have been contradictory (Fukumoto et al., 2003, Sobow et al., 2005, Ertekin-Taner et al., 2008, Lopez et al., 2008). The reason for this discrepancy remains unclear, although blood or CSF Aβ levels could alter according to AD stage (Kawarabayashi et al., 2001). Although the results have not been consistent, several epidemiological studies have indicated that changes in peripheral levels of Aβ, especially higher Aβ40/Aβ42 ratios, represent a risk for future onset of AD (Mayeux et al., 1999, Mayeux et al., 2003, van Oijen et al., 2006, Graff-Radford et al., 2007, Schupf et al., 2008, Lambert et al., 2009). Peripheral Aβ levels in elderly patients with depression have been found to be inconsistent (Pomara et al., 2006, Sun et al., 2007, Sun et al., 2008). We previously reported that serum Aβ40/Aβ42 ratios were significantly higher in patients with major depressive disorder (MDD) than in healthy comparisons, and this difference is seen in both elderly and younger subjects (Kita et al., 2009, Baba et al., 2012). We suggest that Aβ metabolism may be affected in depression, and this may indicate why even early-onset depression is a risk factor for developing AD. However, the mechanism of the association between depression and Aβ is still unclear.