Alterations of Ca super(2+)-responsive proteins within cholinergic neurons in aging and Alzheimer's disease super()

• Published in: Neurobiology of aging 2014-06, Vol.35 (6), p.1325-1333
• Main Authors: Riascos, David, Nicholas, Alexander, Samaeekia, Ravand, Yukhananov, Rustam, Mesulam, M-Marsel, Bigio, Eileen H, Weintraub, Sandra, Guo, Ling, Geula, Changiz
• Format: Article
• Language: English
• ISSN: 0197-4580
• DOI: 10.1016/j.neurobiolaging.2013.12.017

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 sub(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 Ca super(2+)-responsive proteins Ca super(2+)/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 delta , and GAP43 proteins in BF homogenates in aging and AD. Activated mu -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 mu -calpain was confirmed using proteolytic fragments of its substrate spectrin. Substantial age- and AD-related alterations in Ca super(2+)-sensing proteins most likely contribute to selective vulnerability of BFCN to degeneration in AD.