Calpain inhibition prevents amyloid-β-induced neurodegeneration and associated behavioral dysfunction in rats

Abstract

Amyloid-β (Aβ) is toxic to neurons and such toxicity is – at least in part – mediated via the NMDA receptor. Calpain, a calcium dependent cystein protease, is part of the NMDA receptor-induced neurodegeneration pathway, and we previously reported that inhibition of calpain prevents excitotoxic lesions of the cholinergic nucleus basalis magnocellularis of Meynert. The present study reveals that inhibition of calpain is also neuroprotective in an in vivo model of Aβ oligomer-induced neurodegeneration in rats. Aβ-induced lesions of the nucleus basalis induced a significant decrease in the number of cholinergic neurons and their projecting fibers, as determined by analysis of choline-acetyltransferase in the nucleus basalis magnocellularis and cortical mantle of the lesioned animals. Treatment with the calpain inhibitor A-705253 significantly attenuated cholinergic neurodegeneration in a dose-dependent manner. Calpain inhibition also significantly diminished the accompanying neuroinflammatory response, as determined by immunohistochemical analysis of microglia activation. Administration of β-amyloid markedly impaired performance in the novel object recognition test. Treatment with the calpain inhibitor, A-705253, dose-dependently prevented this behavioral deficit. In order to determine whether pre-treatment with the calpain inhibitor is necessary to exhibit its full protective effect on neurons we induced Aβ toxicity in primary neuronal cultures and administered A-705253 at various time points before and after Aβ oligomer application. Although the protective effect was higher when A-705253 was applied before induction of Aβ toxicity, calpain inhibition was still beneficial when applied up to 1 h post-treatment. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of Aβ oligomer-induced neuronal decline and associated cognitive deterioration.