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  • However to date all clinical

    2018-10-23

    However, to date, all clinical trials designed to low levels of Aβ by either blocking activity of β or γ secretases, preventing Aβ aggregation, or promoting Aβ clearance by immunotherapy have failed (Cummings et al., 2014) emphasizing an urgent need to find new therapies for AD. One of the emerging therapeutic approaches involves modulation of cellular energetics that includes activation of AMP-activated protein kinase (AMPK), a master regulator of intracellular energy metabolism (Shirwany and Zou, 2014). AMPK activation was shown to promote neuronal survival after the exposure to Aβ peptides, induce autophagy-dependent degradation of Aβ, and reduce tau phosphorylation (Park et al., 2012; Salminen et al., 2011; Vingtdeux et al., 2010, 2011). Resveratrol-induced activation of AMPK reduced cognitive impairment in SAMP8 mouse model of AD (Porquet et al., 2013). AMPK activation is also linked to an increase in life span in model organisms (Kenyon, 2010; Mair et al., 2011; Salminen and Kaarniranta, 2012), and to prevention of obesity and insulin resistance, conditions that significantly and independently increase risk of AD (Hardie, 2007; Profenno et al., 2010). Metformin, an FDA approved drug to treat type 2 diabetes and potent activator of AMPK (Pernicova and Korbonits, 2014), reduces tau phosphorylation and improves neuronal insulin signaling and AD-related neuropathological changes in vitro (Gupta et al., 2011; Kickstein et al., 2010). However, activation of AMPK has been shown to contribute to AD pathology and cause Anisomycin cost damage in AD mice (Cai et al., 2012; Mairet-Coello et al., 2013). Similar, metformin was also shown to increase Aβ levels by up-regulating the activity of beta-site APP-cleaving enzyme 1 (BACE1), which could account for increased risk of AD development in diabetic patients treated with metformin (Imfeld et al., 2012; Moore et al., 2013). Thus, the development of safe metabolic modulators for AD treatment represents a considerable challenge. Previously, we have synthesized several tricyclic pyrone compounds based on the structures of pyripyropene A, a potent acyl-CoA:cholesterol O-acyltransferase inhibitor (Omura et al., 1993), and arisugacin, a potent acetylcholinesterase inhibitor (Hua et al., 1997; Omura et al., 1995). One of the compounds, CP2, was found to attenuate Aβ-induced toxicity in primary cortical neurons (Maezawa et al., 2006) and reduce Aβ aggregation in 5× transgenic animal model of familial AD (Hong et al., 2009). Here, we report that mild inhibition of mitochondrial complex I with tricyclic pyrone compound CP2 reduces levels of both Aβ and pTau and averts the development of cognitive and behavior phenotype in three mouse models of FAD. We identified CP2 binding site in the redox center of complex I, and defined the molecular mechanism that involves activation of AMPK and restoration of axonal trafficking. Our results provide compelling evidence that modulation of complex I activity represent promising and alternative therapeutic strategy for AD.
    Material and Methods
    Results
    Discussion We present evidence that modulation of cellular energetics via mild inhibition of mitochondrial complex I reduces levels of both Aβ and pTau and averts the development of cognitive phenotype in multiple FAD mice. Using low-mass molecular dynamics simulations and multiple biochemical approaches, we identified that CP2 competes with FMN for binding to the redox center of human mitochondrial complex I. We conducted comprehensive animal studies utilizing three distinct, transgenic mouse models of FAD with early and late disease onset and two treatment regimens that demonstrate unequivocal protection of mice against cognitive decline as well as enhanced vigor and fecundity relative to untreated groups. We also performed in-depth evaluation of molecular mechanisms in vitro and in vivo determining that changes in cellular energetics led to an increase in AMP/ATP ratio and activation of AMPK, with subsequent reduction in GSK3β and restoration of axonal trafficking (Fig. 7J). Our findings demonstrate that modulation of mitochondrial function by small-molecule therapeutics could effectively and safely modify or prevent the development of disease validating promising and alternative therapeutic strategy for AD that may offer a practical treatment to patients.