title: Role of hippocalcin in mediating Aβ toxicity.
abstract: Alzheimer's disease (AD) is the most common cause of dementia, and amyloid-β (Aβ) plaques and tau-containing tangles are its histopathological hallmark lesions. These do not occur at random; rather, the neurodegenerative process is stereotyped in that it is initiated in the entorhinal cortex and hippocampal formation. Interestingly, it is the latter brain area where the calcium-sensing enzyme hippocalcin is highly expressed. Because calcium deregulation is a well-established pathomechanism in AD, we aimed to address the putative role of hippocalcin in human AD brain and transgenic mouse models. We found that hippocalcin levels are increased in human AD brain and in Aβ plaque-forming APP23 transgenic mice compared to controls. To determine the role of hippocalcin in Aβ toxicity, we treated primary cultures derived from hippocalcin knockout (HC KO) mice with Aβ and found them to be more susceptible to Aβ toxicity than controls. Likewise, treatment with either thapsigargin or ionomycin, both known to deregulate intracellular calcium levels, caused an increased toxicity in hippocampal neurons from HC KO mice compared to wild-type. We found further that mitochondrial complex I activity increased from 3 to 6months in hippocampal mitochondria from wild-type and HC KO mice, but that the latter exhibited a significantly stronger aging phenotype than wild-type. Aβ treatment induced significant toxicity on hippocampal mitochondria from HC KO mice already at 3months of age, while wild-type mitochondria were spared. Our data suggest that hippocalcin has a neuroprotective role in AD, presenting it as a putative biomarker.
authors.affiliation: Alzheimer's & Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, 100 Mallett St, Camperdown, NSW 2050, Australia. limy@med.usyd.edu.au
authors.forename: Yun-An
authors.initials: YA
authors.lastname: Lim
authors.forename: Maria
authors.initials: M
authors.lastname: Giese
authors.forename: Claire
authors.initials: C
authors.lastname: Shepherd
authors.forename: Glenda
authors.initials: G
authors.lastname: Halliday
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Ken
authors.initials: K
authors.lastname: Takamatsu
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
mesh_terms: D000367:Age Factors; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051597:Hippocalcin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D051597:Hippocalcin; D002118:Calcium