SUMMARY
Currently, ~5.8 million Americans suffer from Alzheimer's disease (AD)1 and there remain no approved
therapeutics to lessen the associated neuronal dysfunction and cell death. Various AD clinical trials targeting
the “amyloid cascade” have proven unsuccessful, suggesting a dire need to rethink AD disease progression.
Alterations in cellular calcium (iCa2+) and mitochondrial function are reported as critical molecular contributors
to AD pathogenesis. Our lab has previously shown that genetic modulation of either mCa2+ uptake or efflux is a
powerful way to limit mitochondrial dysfunction and cell death in the context of cell stress featuring elevated
iCa2+. As causal evidence of impaired mCa2+ exchange in AD, we generated multiple mutant mouse models to
modulate neuronal NCLX expression, the primary mechanism for 2+ efflux in excitable cells, and
mCa
discovered that impaired mitochondrial calcium efflux proceeds neuropathology and memory decline in 3xTg-
AD mouse model. In addition to alterations in
mCa
2+ efflux, we also discovered significant proteomic remodeling
of the mitochondrial calcium uniporter channel (mtCU). The mtCU is required for acute Ca2+ uptake into the
mitochondrial matrix where it regulates mitochondrial function. The mtCU is a multiprotein channel, consisting
of pore-forming, scaffold, and regulatory components. To date, there are no published in vivo studies using
genetic models to define the contribution of mCa2+ uptake with AD disease progression and given our published
findings regarding the role of mCa2+ efflux in AD pathogenesis17, it's imperative that we mechanistically define
the mCa2+ uptake pathway prior to proceeding with therapeutic development. In this project, we hypothesize
that mCa2+overload is a primary contributor to AD pathology by promoting metabolic dysfunction and
neuronal cell death, and that reducing mtCU-dependent mCa2+ uptake will impede neurodegeneration
and AD pathogenesis. Further, using complex mutant mouse models we will systematically define the
mitochondrial metabolomic and proteomic changes associated with AD progression and alterations in mCa2+
flux. Optimally, these studies will identify new therapeutic targets for the treatment of AD.