New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer’s disease

Abstract

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.

Mitochondrial Permeability Transition, Cell Death and Neurodegeneration

“…Therefore, in the pursuit of discovering novel inhibitors targeting CypD and mPTP, researchers have used various approaches, ranging from the large-scale screening of substances available in FDA-approved and other libraries [43,44] to the de novo development of new peptides [45]. Some of the new mPTP inhibitors (Ebselen) have already proved their efficiency in mouse models of Alzheimer's disease [44]. From the very beginning until now CypD has been the only protein whose forming role in the PTP phenomenon has been 100% proven.…”

“…Moreover, CsA is quite toxic, and its application has a lot of side effects, so research and development of new non-immunosuppressive CypD and mPTP inhibitors remains an important and challenging task. Therefore, in the pursuit of discovering novel inhibitors targeting CypD and mPTP, researchers have used various approaches, ranging from the large-scale screening of substances available in FDA-approved and other libraries [43,44] to the de novo development of new peptides [45]. Some of the new mPTP inhibitors (Ebselen) have already proved their efficiency in mouse models of Alzheimer's disease [44].…”

“…Based on the importance of mPTP in the pathology of Alzheimer's disease, a number of studies have focused on the study of novel molecules for the inhibition of the permeability transition and neuroprotection [44,64].…”