Role of calpain and caspase in beta-amyloid-induced cell death in rat primary septal cultured neurons.
The invariant characteristic features associated with Alzheimer's disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid beta (Abeta) peptide, intracellular neurofibrillary tangles containing hyper-phosphorylated tau protein and the loss of basal forebrain cholinergic neurons. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that in vivo accumulation of Abeta(1-42) may initiate the process of neurodegeneration observed in AD brains. However, the cause of degeneration of the basal forebrain cholinergic neurons and their association to Abeta peptides or phosphorylated tau protein have not been clearly established. In the present study, using rat primary septal cultures, we have shown that Abeta(1-42), in a time (1-48 h) and concentration (0.01-20 microM)-dependent manner, induce toxicity in cultured neurons. Subsequently, we have demonstrated that Abeta toxicity is mediated via activation of cysteine proteases, i.e., calpain and caspase, and proteolytic breakdown of their downstream substrates tau, microtubule-associated protein-2 and alpha II-spectrin. Additionally, Abeta-treatment was found to induce phosphorylation of tau protein along with decreased levels of phospho-Akt and phospho-Ser(9)glycogen synthase kinase-3beta. Exposure to specific inhibitors of caspase or calpain can partially protect cultured neurons against Abeta-induced toxicity but their effects are not found to be additive. These results, taken together, suggest that Abeta peptide can induce toxicity in rat septal cultured neurons by activating multiple intracellular signaling molecules. Additionally, evidence that inhibitors of caspase and calpains can partially protect the cultured basal forebrain neurons raised the possibility that their inhibitors could be of therapeutic relevance in the treatment of AD pathology.
Wei
Z
Z
Department of Psychiatry, Alberta Centre for Prion and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
Song
M S
MS
MacTavish
D
D
Jhamandas
J H
JH
Kar
S
S
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008855:Microscopy, Electron, Scanning / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D020665:Septum of Brain / Q000166:cytology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C033668:calpastatin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; D020169:Caspases; C022616:thiazolyl blue