Summary/Abstract We propose to conduct rigorous evaluation of the role AMP-activated protein kinase (AMPK) plays in the development of Alzheimer?s Disease (AD) and provide compelling evidence to justify activation of AMPK as a therapeutic strategy for AD. AMPK is a highly conserved serine/threonine protein kinase that is activated by elevated AMP/ATP ratio. AMPK activates a host of integrated physiological responses including stimulation of energy production and mitochondrial biogenesis, activation of anti-oxidant response, and induction of autophagy via inhibition of mTOR. Since of these processes are dysfunctional in AD, the loss of AMPK activity could contribute AD pathogenesis and activation of AMPK could be beneficial. However, experiments that target AMPK in various animal models of AD have yielded ambiguous outcomes underscoring the importance of rigorous evaluation of the pathological significance of AMPK in AD. We demonstrated that partial inhibition of mitochondrial Complex I (MCI) activity with small molecules (CP2) developed in Dr. Trushina laboratory induces stress resilience pathways including AMPK activation and enhancement of mitochondrial biogenesis and cellular energetics. Importantly, collaborative efforts between Drs. Lee and Trushina have shown that CP2 treatment can attenuate amyloid dependent neurodegeneration in the Tg2576/PS1 mouse model of AD. While forebrain neurodegeneration is not a robust feature of most Tg mouse models of AD, we found that cerebral A? deposition in AD mouse models are associated with progressive degeneration of monoaminergic (MAergic) neurons, recapitulating the early degeneration of serotonergic (5-HT) and noradrenergic (NA) neurons seen in human AD patients. Using the state of art mouse models and CP2, we propose to (a) determine whether AMPK activity regulates onset and progression of AD pathology in vivo, and (b) establish to what extent loss of AMPK in neurons vs. astrocytes modulate the AD development, (c) examine whether therapeutic effect of CP2, particularly the progressive neurodegeneration, is AMPK-dependent and is facilitated in neurons or astrocytes. We will develop multiple mouse models with conditional knock out of regulatory ?1 and ?2 AMPK subunits in the whole brain using the nestin-Cre as a driver; specifically in astrocytes using pGFAP-CreERT or in neurons using SLICK- H mice (pThy1-CreERT). We will examine if constitutive loss of AMPK in brain of AP/PS Tg mouse model exacerbates AD pathology including MAergic neurodegeneration. We will also determine if the loss of AMPK directly impacts mitochondrial biology and bioenergetics in the AP/PS model. The proposed studies are based on strong premise and will provide rigorous test of the hypothesis using innovative cell biology, biochemistry and imaging techniques, and genetic interventions. The outcomes will provide the critical evidence to justify AMPK as a therapeutic target for AD.
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