Cyclophilin D (CypD) promotes mitochondrial impairment, synaptic defects, cognitive loss, and tau pathology during aging.

Mitochondrial dysfunction is considered a hallmark of the aging brain, and this organelle can be affected by several neurodegenerative conditions, leading to slowed bioenergetics and reduced energy production. These processes will affect neuronal communication and synaptic plasticity, generating cognitive decline during aging. Interestingly, we previously observed that mitochondrial dysfunction can be influenced by pathological forms of tau, which are posttranslational modifications of this protein implicated in neurodegeneration and aging. In this context, accumulating evidence indicates that mitochondrial impairment may be associated with activation of the mitochondrial permeability transition pore (mPTP). mPTP has been described as a critical regulator of mitochondrial function, and its pathological activation by cyclophilin D (CypD) induces neurodegeneration and reduces brain function. However, the role of CypD/mPTP on cognitive decline and its implications on tau pathology and neurodegeneration during aging has not been studied. Therefore, we evaluated the contribution of CypD/mPTP in mitochondrial dysfunction, cognitive decline, and tau pathology observed in aging animals. Aging mice lacking CypD expression (CypD-/-) (24-month-old) showed better cognitive performance, improved mitochondrial bioenergetics, increased ATP production, and mPTP closure compared with age-matched wild-type mice (24-month-old) with endogenous expression of CypD. Consequently, hippocampal tissue from aged wild-type animals showed a significant decrease in presynaptic protein levels (SV2) compared to aged CypD-/- animals. More importantly, CypD ablation prevented caspase-3 cleaved tau accumulation in the cytosolic and mitochondrial fractions of hippocampal tissue from 24-month-old mice, in contrast with wild-type aged mice that expressed endogenous CypD. These novel results indicate that CypD acts as a neurodegenerative promoter, inducing synaptic defects and cognitive decline by opening mPTP and mitochondrial dysfunction. More importantly, CypD contributes to the neurodegenerative effects of caspase-3-cleaved tau during aging, suggesting a novel neurodegenerative target induced by tau pathology.