Oligomycin Sensitivity Conferring Protein and Mitochondrial Deficits in the Aging Brain and Alzheimer's Disease



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Brain aging is the strongest risk factor for Alzheimer’s Disease (AD), in particular its sporadic form. However, the mechanism underlying the development of AD as a result of aging remains elusive. In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD, and are considered pivotal in inducing synaptic injury and neuronal stress. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore (mPTP) opening. Here, we have found that increase in CypD expression, enhanced CypD/OSCP interaction and selective loss of OSCP are prominent brain mitochondrial changes in aging and AD mice. Furthermore, Aβ toxicity in AD-related pathophysiology augments CypD/OSCP interaction and exacerbates mitochondrial dysfunction. Moreover, the ablation of CypD relieves OSCP changes in the aging brain and 5xFAD mice along with preserved F1FO ATP synthase function, restored mitochondrial bioenergetics as well as improved mouse cognition (in AD mice). This suggests that CypD is a regulator of OSCP expression and promotes OSCP deficits, which causes mitochondrial dysfunction in brain aging and AD-related conditions. To further support our findings of CypD-mediated OSCP changes in the development of mitochondrial deficits in AD, we restored OSCP expression in AD mice by utilizing an original neuron-specific OSCP overexpressing mice. OSCP overexpressing AD mice exhibited significant protection from F1FO ATP synthase deregulation. Importantly, such protection accompanies preserved mitochondrial bioenergetics and blunted mitochondrial permeability transition pore (mPTP) formation as well as restored synaptic plasticity and transmission & improved cognition in AD mice. Thus, our findings collectively suggest that OSCP-associated mitochondrial deficits are common mechanisms in brain aging and AD and preserving OSCP expression has the potential to be a promising therapeutic strategy to correct mitochondrial dysfunction in brain aging and AD.



Alzheimer's disease, Brain -- Aging, Mitochondrial pathology