The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration.
Recently, we have shown that the microtubule-associated protein tau is essential for beta-amyloid (Abeta)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates Abeta-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated Abeta induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced Abeta-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that Abeta-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate Abeta-induced neurotoxicity.
Park
So-Young
SY
Department of Cell and Molecular Biology, Feinberg School of Medicine, and Institute for Neuroscience, Northwestern University, Chicago, Illinois 60611, USA.
Ferreira
Adriana
A
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006868:Hydrolysis; D008970:Molecular Weight; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D010446:Peptide Fragments; D016875:tau Proteins; D002154:Calpain; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases