Alterations of Ca²⁺-responsive proteins within cholinergic neurons in aging and Alzheimer's disease.
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 Ca(2+)-responsive proteins Ca(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, 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 Ca(2+)-sensing proteins most likely contribute to selective vulnerability of BFCN to degeneration in AD.
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
David
D
Riascos
Department of Medicine, Harvard Medical School and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Alexander
A
Nicholas
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Ravand
R
Samaeekia
Precision Biosystems, Mansfield, MA, USA.
Rustam
R
Yukhananov
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
M-Marsel
MM
Mesulam
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Eileen H
EH
Bigio
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Sandra
S
Weintraub
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Ling
L
Guo
Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. Electronic address: c-geula@northwestern.edu.
Changiz
C
Geula
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D064092:Calbindin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000378:metabolism; D055815:Young Adult
D064092:Calbindin 1; D019922:GAP-43 Protein; D012313:RNA; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1; D002154:Calpain
Basal forebrain; CaMKI; Calbindin-D(28K); Calpain; Cholinergic system; GAP43; Proteolysis