title: Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of Aβ in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by pathological deposits of β-amyloid (Aβ) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium, and accumulating data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here, we show that elevated calpain, but not caspase-3, activity is a prominent feature of AD brain. In addition, we observe increased calpain-mediated cleavage of NCX3, but not a related family member NCX1, in AD brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of NCX3 proteolysis correlated significantly with amounts of Aβ1-42. We also show that exposure of primary cortical neurons to oligomeric Aβ1-42 results in calpain-dependent cleavage of NCX3, and we demonstrate that loss of NCX3 function is associated with Aβ toxicity. Our findings suggest that Aβ mediates calpain cleavage of NCX3 in AD brain and therefore that reduced NCX3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in AD.
authors.affiliation: Institute of Psychiatry, Department of Neuroscience, King's College London, London, SE5 8AF, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Atherton
authors.forename: Ksenia
authors.initials: K
authors.lastname: Kurbatskaya
authors.forename: Marie
authors.initials: M
authors.lastname: Bondulich
authors.forename: Cara L
authors.initials: CL
authors.lastname: Croft
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Garwood
authors.forename: Resham
authors.initials: R
authors.lastname: Chhabra
authors.forename: Selina
authors.initials: S
authors.lastname: Wray
authors.forename: Andreas
authors.initials: A
authors.lastname: Jeromin
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011180:Postmortem Changes; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013049:Spectrin / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D024801:Tauopathies / Q000201:enzymology / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D016376:Oligonucleotides, Antisense; D021122:Protein Subunits; C101832:SLC38A3 protein, human; C491102:Slc8a3 protein, rat; D019831:Sodium-Calcium Exchanger; D013049:Spectrin; C033668:calpastatin; D002154:Calpain; D053148:Caspase 3
keywords: Alzheimer's disease; beta-amyloid; calcium; calpain; sodium calcium exchanger; tau
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