Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer’s pathology

Abstract Background Oligomycin-sensitivity conferring protein (OSCP) is a critical subunit of mitochondrial F1Fo ATP synthase. OSCP dysfunction has been observed in Alzheimer’s disease (AD) brains and a mouse model with AD-like brain amyloidosis (5xFAD mice). However, whether OSCP dysfunction constitutes a key mitochondrial defect contributing to synaptic injury in AD-related conditions has not been comprehensively investigated. Methods Here, we used a 5xFAD mouse model with OSCP overexpression in neurons (Thy-1 OSCP/5xFAD mice) and cultured neurons from OSCP overexpressing pups in the study. We performed biochemical, immunohistochemical, live cell imaging and electrophysiological as well as behavioral analyses.Results We found that preserved OSCP expression with reduced interaction of amyloid beta (Aβ) with membrane-bound OSCP in Thy-1 OSCP/5xFAD mice. OSCP overexpression also alleviated F1Fo ATP synthase deregulation and preserved mitochondrial function. Moreover, OSCP modulation conferred resistance to Aβ-mediated defects in axonal mitochondrial dynamics & motility. Consistent with protected neuronal mitochondrial function, OSCP overexpression ameliorated hippocampal synaptic injury in 5xFAD mice as demonstrated by preserved synaptic density and synaptic transmission, reduced complement-dependent synapse elimination, leading to improved spatial learning and memory. Conclusion Our findings show the consequences of OSCP dysfunction in the development of synaptic stress in AD-related conditions and they implicate OSCP modulation as a potential therapeutic strategy.