Molecular mechanisms of the Alzheimer’s risk gene Unc5c in neuronal death

A recently discovered autosomal dominant mutation (T835M) in the death domain hinge region of Unc5c segregates with late-onset AD and in vitro increases cell death in response to Aß. Since the effects of Unc5c T835M in an AD animal model have yet to be explored, we will cross Unc5c T835M knock in (KI) mice with 5XFAD mice that exhibit amyloid pathology and neuron loss. Hypothesis: Unc5c T835M will exacerbate neuron death in 5XFAD brain via increased sensitivity to Aß-induced neurotoxicity and Unc5c death domain activation. Methods: Aß42-treated Unc5c T835M KI primary neurons and 5XFAD;Unc5cKI/KI brains will be assessed for cell death pathways (caspase activation, LDH release, TUNEL staining, propidium iodide staining, westerns, IHC, RNAseq), memory testing in 5XFAD;Unc5cKI/KI mice, and western and IHC in human AD brain samples.