Mitochondrial dysfunction is an early pathological feature of Alzheimer disease (AD) and plays a crucial role in the development and progression of AD. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore (mPTP), leading to mitochondrial dysfunction and cell death. Blocking mPTP opening by inhibiting CypD activity is a promising therapeutic approach for AD. However, there is currently no effective CypD inhibitor for AD, with previous candidates demonstrating high toxicity, poor ability to cross the blood-brain barrier, compromised biocompatibility, and low selectivity. Here, we report a new class of nontoxic and biocompatible CypD inhibitor, Ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-Ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on AD mitochondrial and glycolytic bioenergetics in AD-derived mitochondrial cybrid cells, an ex-vivo human sporadic AD mitochondrial model, and on synaptic function, inflammatory response, and learning and memory in AD mouse models. Inhibition of CypD by Ebselen protects against sporadic AD- and amyloid beta (Aβ)-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of AD mouse models, which is linked to CypD-related mPTP formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including AD, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.
