Role of hippocalcin in mediating Aβ toxicity

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1822

Article

Lim, Yun-An¹  Giese, Maria²  Shepherd, Claire³  Halliday, Glenda^3,4  Kobayashi, Masaaki⁵  Takamatsu, Ken⁵  Staufenbiel, Matthias⁶  Eckert, Anne²  Goetz, Juergen¹ 

[1] Univ Sydney, Brain & Mind Res Inst, Alzheimers & Parkinsons Dis Lab, Camperdown, NSW 2050, Australia

[2] Univ Basel, Psychiat Univ Clin Basel, Neurobiol Lab, CH-4012 Basel, Switzerland

[3] Neurosci Res Australia, Sydney, NSW 2031, Australia

[4] Univ New S Wales, Sydney, NSW 2031, Australia

[5] Toho Univ, Sch Med, Dept Physiol, Ohta Ku, Tokyo, Japan

[6] Novartis Inst Biomed Res, CH-4002 Basel, Switzerland

关键词: Alzheimer;    Amyloid;    Calcium;    Pathogenesis;    Toxicity;    Transgenic mice;   

DOI  :  10.1016/j.bbadis.2012.04.007

来源: Elsevier

【 摘 要 】

Alzheimer's disease (AD) is the most common cause of dementia, and amyloid-beta (A beta) 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 A beta plaque-forming APP23 transgenic mice compared to controls. To determine the role of hippocalcin in to toxicity, we treated primary cultures derived from hippocalcin knockout (HC KO) mice with A beta and found them to be more susceptible to A beta 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 6 months in hippocampal mitochondria from wild-type and HC KO mice, but that the latter exhibited a significantly stronger aging phenotype than wild-type. A beta treatment induced significant toxicity on hippocampal mitochondria from HC KO mice already at 3 months 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. (C) 2012 Elsevier B.V. All rights reserved.

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