The Role of MICU3 in Alzheimer's Disease Pathogenesis

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PROJECT ABSTRACT 6.2M Americans over the age of 65 suffer from Alzheimer’s disease (AD) and this number expected to double in ~30 years. AD is characterized by aphasia, loss of fine and gross motor function, and rapid cognitive decline. The widely favored “amyloid hypothesis” of AD posits that accumulation of fibrillar amyloid beta (Aβ) plaques in the brain parenchyma drives AD pathogenesis. However, the amyloid pathway has proven to be an ineffective therapeutic target in numerous clinical trials and AD remains clinically intractable, highlighting the urgent need for deeper understanding of the underlying mechanisms of disease. Our lab previously reported that mitochondrial calcium (mCa2+) overload promotes AD pathogenesis. mCa2+ homeostasis is maintained through regulation of mCa2+ uptake through the mitochondrial calcium uniporter channel (mtCU) and mCa2+ efflux through the mitochondrial Na+/Ca2+ exchanger (NCLX). Human cortex from sporadic AD patients demonstrates >70% reduction in NCLX expression. Genetic rescue of mCa2+ efflux via hippocampal neuron-specific expression of NCLX protects against mCa2+ overload, ROS-stress, Aβ and tau deposition, and cognitive decline in AD mutant mice. We interpret remodeling of mCa2+ transport as a compensatory response to an early pathologic stress (e.g., energetic crisis, aging, genetic predisposition) to increase ATP bioavailability. Over time, this response turns maladaptive and promotes pathologic mCa2+ overload. mCa2+ overload causes excessive production of reactive oxygen species (ROS), metabolic derangement, and cell death, all hallmarks of AD. Although a robust connection between neuronal mCa2+ overload and AD pathogenesis has been established, how altered regulation of mCa2+ uptake promotes or protects against AD pathology remains completely unexplored. Our preliminary data demonstrates MICU3 expression is significantly reduced by ~50% in multiple cortical regions of samples isolated from sporadic AD patients. Further, MICU3 expression is reduced >90% in the cortex of 1 year-old. 3xTg-AD mutant mice. This proposal hypothesizes that loss of neuronal Micu3 contributes to aberrant mtCU-mediated mCa2+ uptake, resulting in mCa2+ overload, metabolic derangement, neuronal dysfunction, and cognitive decline in AD. To address this hypothesis we will utilize newly generated neuron-specific MICU3 knockout mouse lines to measure if knockout of MICU3 alone is sufficient to cause neurodegeneration. Subsequently, we will use our newly developed cre-inducible MICU3 overexpression mouse line to see if rescuing MICU3 levels shortly after onset of cognitive decline in the APPNL-G-F mouse model of AD is sufficient to mitigate or reverse AD pathology. These studies will be followed up with a series of mechanistic in vitro studies to determine the molecular mechanism of MICU3-mediated neuronal dysfunction in AD. The role of MICU3 in physiology and disease states, including AD, is unknown; coupled with our findings that altered mCa2+ handling is a pathologic feature of and promising therapeutic target for AD provides strong rationale for this proposal.