Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression.
Increased activity of calpains is implicated in synaptic dysfunction and neurodegeneration in Alzheimer's disease (AD). The molecular mechanisms responsible for increased calpain activity in AD are not known. Here, we demonstrate that disease progression is propelled by a marked depletion of the endogenous calpain inhibitor, calpastatin (CAST), from AD neurons, which is mediated by caspase-1, caspase-3, and calpains. Initial CAST depletion focally along dendrites coincides topographically with calpain II and ERK 1/2 activation, tau cleavage by caspase-3, and tau and neurofilament hyperphosphorylation. These same changes, together with cytoskeletal proteolysis and neuronal cell death, accompany CAST depletion after intrahippocampal kainic acid administration to mice, and are substantially reduced in mice overexpressing human CAST. Moreover, CAST reduction by shRNA in neuronal cells causes calpain-mediated death at levels of calcium-induced injury that are sublethal to cells normally expressing CAST. Our results strongly support a novel hypothesis that CAST depletion by multiple abnormally activated proteases accelerates calpain dysregulation in AD leading to cytoskeleton disruption and neurodegeneration. CAST mimetics may, therefore, be neuroprotective in AD.
Rao
Mala V
MV
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962, USA.
Mohan
Panaiyur S
PS
Peterhoff
Corrinne M
CM
Yang
Dun-Sheng
DS
Schmidt
Stephen D
SD
Stavrides
Philip H
PH
Campbell
Jabbar
J
Chen
Yuanxin
Y
Jiang
Ying
Y
Paskevich
Peter A
PA
Cataldo
Anne M
AM
Haroutunian
Vahram
V
Nixon
Ralph A
RA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002461:Cell Line, Transformed; D003599:Cytoskeleton / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011180:Postmortem Changes; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection / Q000379:methods
D002135:Calcium-Binding Proteins; D018690:Excitatory Amino Acid Agonists; D034741:RNA, Small Interfering; C033668:calpastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D002154:Calpain; D020169:Caspases; D007608:Kainic Acid