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

• Published in: Neurobiology of aging Vol. 35; no. 6; pp. 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: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2014
• Subjects: Adult; Aged; Aged, 80 and over; Aging - genetics; Aging - pathology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Basal forebrain; Calbindin 1 - deficiency; Calbindin 1 - genetics; Calbindin 1 - metabolism; Calbindin-D28K; Calcium-Calmodulin-Dependent Protein Kinase Type 1 - genetics; Calcium-Calmodulin-Dependent Protein Kinase Type 1 - metabolism; Calpain; Calpain - metabolism; CaMKI; Cholinergic Neurons - metabolism; Cholinergic Neurons - pathology; Cholinergic system; Female; GAP-43 Protein - metabolism; GAP43; Humans; Immunohistochemistry; Internal Medicine; Male; Middle Aged; Nerve Degeneration - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurofibrillary Tangles - metabolism; Neurofibrillary Tangles - pathology; Neurology; Prosencephalon - metabolism; Prosencephalon - pathology; Proteolysis; RNA - metabolism; Young Adult; CaMKI; GAP43; Proteolysis; Calpain; Basal forebrain; Calbindin-D 28K; Cholinergic system; Calbindin-D28K; Calbindin-D(28K)
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2013.12.017

Abstract 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-D28K (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, CaMKIδ, and GAP43 proteins in BF homogenates in aging and AD. Activated μ-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 μ-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.