Abstract

Abnormal tau modifications are one of the main contributors to neurodegenerative processes present during Alzheimer's disease (AD). In this context, truncated tau by caspase-3, a pathological tau form, affects mitochondrial function and antioxidant regulation, contributing to synaptic and cognitive impairment in AD mouse models. We previously showed that the presence of caspase-3 cleaved tau promotes mitochondrial impairment in neuronal cells, where Cyclophilin-D (CypD) protein could be a crucial element. CypD is considered the master regulator of mitochondrial permeability transition pore (mPTP) opening, and its ablation prevents neurodegenerative and cognitive damage induced by ??amyloid in mouse models of AD. However, the possible role of CypD in the neurodegenerative processes mediated by caspase-3-cleaved tau has not been explored. Here, we use tau (?/?) and CypD (?/?) knock-out mice that were subjected to right-side hippocampal stereotaxic injection to induce GFP (AAV-Syn-GFP), full-length (AAV-Syn-GFP-T4) or caspase-3-cleaved (AAV-Syn-GFP-T4C3) tau expression. Then, cognitive performance, synaptic architecture, and hippocampal mitochondrial function were evaluated two months later. We observed that caspase-3 cleaved tau expression inducing cognitive decline, vesicle and synaptic protein deregulation, and mitochondrial impairment generated by the mPTP opening. More interestingly, when caspase-3 cleaved tau was expressed in the hippocampus of CypD (?/?) mice, cognitive decline, synaptic impairment, and mitochondrial damage mediated by mPTP were prevented, demonstrating a novel role of CypD in neurodegenerative changes induced by truncated tau in AD. © 2025 Elsevier Inc.