# Collapsin Response Mediator Protein 2 (CRMP2) Modulates Induction of the Mitochondrial Permeability Transition Pore in a Knock-In Mouse Model of Alzheimer’s Disease

## TL;DR

This study shows that a protein called CRMP2, when hyperphosphorylated, affects mitochondrial function in Alzheimer's disease, and a drug candidate may help reduce this effect.

## Contribution

The paper identifies a novel role for hyperphosphorylated CRMP2 in modulating mitochondrial permeability transition pore (PTP) opening in Alzheimer’s disease.

## Key findings

- Hyperphosphorylated CRMP2 in AD mitochondria promotes PTP opening by dissociating from ANT.
- (S)-LCM reduces CRMP2 hyperphosphorylation and mitigates PTP induction and neuronal death in AD mice.
- The protective effect of (S)-LCM requires upstream cellular mechanisms, as it does not directly block PTP in isolated mitochondria.

## Abstract

Hyperphosphorylated collapsin response mediator protein 2 (CRMP2) is elevated in the cerebral cortex of an APP-SAA knock-in mouse model of Alzheimer’s disease and binds the adenine nucleotide translocase (ANT) in a phosphorylation-dependent manner. We propose that, in Alzheimer’s disease (AD) mitochondria, dissociation of hyperphosphorylated CRMP2 from ANT promotes opening of the permeability transition pore (PTP). We showed that purified ANT, when reconstituted into giant liposomes, forms large calcium-dependent channels resembling the PTP, which are effectively blocked by recombinant, unphosphorylated CRMP2. In synaptic mitochondria isolated from the cortices of APP-SAA knock-in mice and control B6J hAbeta mice, we observed an increased susceptibility to permeability transition pore (PTP) induction in AD mitochondria, accompanied by reduced viability of cultured cortical neurons. Pre-treatment of AD mice with the CRMP2-binding small molecule (S)-lacosamide ((S)-LCM), which prevents CRMP2 hyperphosphorylation and restores its interaction with ANT, attenuated PTP induction and improved neuronal viability. Interestingly, direct application of (S)-LCM to isolated mitochondria failed to suppress PTP induction, indicating that its protective effect requires upstream cellular mechanisms. These findings support a phosphorylation-dependent role for CRMP2 in regulating PTP induction in AD mitochondria and highlight (S)-LCM as a promising therapeutic candidate for mitigating mitochondrial dysfunction and enhancing neuronal viability in AD.