Alterations of Ca²⁺-responsive proteins within cholinergic neurons in aging and Alzheimer's disease

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• 作者：David Riascos^a ; ¹ ; Alexander Nicholas^b ; ¹ ; Ravand Samaeekia^a ; Rustam Yukhananov^c ; M.-Marsel Mesulam^a ; Eileen H. Bigio^a ; Sandra Weintraub^a ; Ling Guo^a ; Changiz Geula^a ; ^{c-geula@northwestern.edu" class="auth_mail}
• 关键词：Calbindin-D28K ; GAP43 ; CaMKI ; Calpain ; Basal forebrain ; Proteolysis ; Cholinergic system
• 刊名：Neurobiology of Aging
• 出版年：June, 2014
• 年：2014
• 卷：35
• 期：6
• 页码：1325-1333
• 全文大小：693 K

文摘

The molecular basis of selective neuronal vulnerability in Alzheimer's disease (AD) remains poorly understood. Using basal forebrain cholinergic neurons (BFCNs) as a model and immunohistochemistry, we have demonstrated significant age-related loss of the calcium-binding protein calbindin-D_28K (CB) from BFCN, which was associated with tangle formation and degeneration in AD. Here, we determined alterations in RNA and protein for CB and the Ca²⁺-responsive proteins Ca²⁺/calmodulin-dependent protein kinase I (CaMKI), growth-associated protein-43 (GAP43), and calpain in the BF. We observed progressive downregulation of CB and CaMKI RNA in laser-captured BFCN in the normal-aged-AD continuum. We also detected progressive loss of CB, CaMKI未, and GAP43 proteins in BF homogenates in aging and AD. Activated 渭-calpain, a calcium-sensitive protease that degrades CaMKI and GAP43, was significantly increased in the normal aged BF and was 10 times higher in AD BF. Overactivation of 渭-calpain was confirmed using proteolytic fragments of its substrate spectrin. Substantial age- and AD-related alterations in Ca²⁺-sensing proteins most likely contribute to selective vulnerability of BFCN to degeneration in AD.