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

doi:10.1016/j.neurobiolaging.2013.12.017

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 journal › Article › peer-review

33 Scopus citations

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-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, 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 language	English (US)
Pages (from-to)	1325-1333
Number of pages	9
Journal	Neurobiology of Aging
Volume	35
Issue number	6
DOIs	https://doi.org/10.1016/j.neurobiolaging.2013.12.017
State	Published - Jun 2014

Funding

We are grateful to Girgis Girgis and Katherine Gasho for expert technical assistance. This work was supported in part by a Zenith Fellows Award (CG) from the Alzheimer's Association and by grants from the National Institute on Aging ( AG014706 and AG027141 ). A portion of the tissue used in these studies was received from the Northwestern University (AG013854) and Massachusetts General Hospital (AG005134) Alzheimer's Disease Centers.

Keywords

Basal forebrain
CaMKI
Calbindin-D
Calpain
Cholinergic system
GAP43
Proteolysis

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Aging
General Neuroscience
Developmental Biology

Access to Document

10.1016/j.neurobiolaging.2013.12.017

Cite this

@article{353df30e898641c1aa113eea7f5a0caf,

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

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.",

keywords = "Basal forebrain, CaMKI, Calbindin-D, Calpain, Cholinergic system, GAP43, Proteolysis",

author = "David Riascos and Alexander Nicholas and Ravand Samaeekia and Rustam Yukhananov and Mesulam, {M. Marsel} and Bigio, {Eileen H.} and Sandra Weintraub and Ling Guo and Changiz Geula",

note = "Funding Information: We are grateful to Girgis Girgis and Katherine Gasho for expert technical assistance. This work was supported in part by a Zenith Fellows Award (CG) from the Alzheimer's Association and by grants from the National Institute on Aging ( AG014706 and AG027141 ). A portion of the tissue used in these studies was received from the Northwestern University (AG013854) and Massachusetts General Hospital (AG005134) Alzheimer's Disease Centers.",

year = "2014",

month = jun,

doi = "10.1016/j.neurobiolaging.2013.12.017",

language = "English (US)",

volume = "35",

pages = "1325--1333",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

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T1 - Alterations of Ca2+-responsive proteins within cholinergic neurons in aging and Alzheimer's disease

AU - Riascos, David

AU - Nicholas, Alexander

AU - Samaeekia, Ravand

AU - Yukhananov, Rustam

AU - Mesulam, M. Marsel

AU - Bigio, Eileen H.

AU - Weintraub, Sandra

AU - Guo, Ling

AU - Geula, Changiz

N1 - Funding Information: We are grateful to Girgis Girgis and Katherine Gasho for expert technical assistance. This work was supported in part by a Zenith Fellows Award (CG) from the Alzheimer's Association and by grants from the National Institute on Aging ( AG014706 and AG027141 ). A portion of the tissue used in these studies was received from the Northwestern University (AG013854) and Massachusetts General Hospital (AG005134) Alzheimer's Disease Centers.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - Basal forebrain

KW - CaMKI

KW - Calbindin-D

KW - Calpain

KW - Cholinergic system

KW - GAP43

KW - Proteolysis

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