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

David Riascos, Alexander Nicholas, Ravand Samaeekia, Rustam Yukhananov, M. Marsel Mesulam, Eileen H. Bigio, Sandra Weintraub, Ling Guo, Changiz Geula*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1325-1333
Number of pages9
JournalNeurobiology of Aging
Issue number6
StatePublished - Jun 2014


  • Basal forebrain
  • CaMKI
  • Calbindin-D
  • Calpain
  • Cholinergic system
  • GAP43
  • Proteolysis

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Aging
  • General Neuroscience
  • Developmental Biology


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