Calpain inhibition prevents amyloid-beta-induced neurodegeneration and associated behavioral dysfunction in rats.
Amyloid-beta (Abeta) 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 Abeta oligomer-induced neurodegeneration in rats. Abeta-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 beta-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 Abeta toxicity in primary neuronal cultures and administered A-705253 at various time points before and after Abeta oligomer application. Although the protective effect was higher when A-705253 was applied before induction of Abeta toxicity, calpain inhibition was still beneficial when applied up to 1h post-treatment. We conclude that inhibition of calpains may represent a valuable strategy for the prevention of Abeta oligomer-induced neuronal decline and associated cognitive deterioration.
Granic
Ivica
I
Molecular Neurobiology, University of Groningen, Haren, The Netherlands.
Nyakas
Csaba
C
Luiten
Paul G M
PG
Eisel
Ulrich L M
UL
Halmy
László G
LG
Gross
Gerhard
G
Schoemaker
Hans
H
Möller
Achim
A
Nimmrich
Volker
V
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000502:physiology; D002478:Cells, Cultured; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
C500488:A-705253; D016229:Amyloid beta-Peptides; D001549:Benzamides; D006023:Glycoproteins; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C039304:calpain inhibitors; D002154:Calpain