Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits

Jorge J. Palop, Brian Jones, Lisa Kekonius, Jeannie Chin, Gui Qiu Yu, Jacob Raber, Eliezer Masliah, Lennart Mucke

Research output: Contribution to journalArticle

291 Citations (Scopus)

Abstract

Transgenic mice expressing human amyloid precursor proteins (hAPP) and amyloid-β peptides (Aβ) in neurons develop phenotypic alterations resembling Alzheimer's disease (AD). The mechanisms underlying cognitive deficits in AD and hAPP mice are largely unknown. We have identified two molecular alterations that accurately reflect AD-related cognitive impairments. Learning deficits in mice expressing familial AD-mutant hAPP correlated strongly with decreased levels of the calcium-binding protein calbindin-D 28k (CB) and the calcium-dependent immediate early gene product c-Fos in granule cells of the dentate gyrus, a brain region critically involved in learning and memory. These molecular alterations were age-dependent and correlated with the relative abundance of Aβ1-42 but not with the amount of Aβ deposited in amyloid plaques. CB reductions in the dentate gyrus primarily reflected a decrease in neuronal CB levels rather than a loss of CB-producing neurons. CB levels were also markedly reduced in granule cells of humans with AD, even though these neurons are relatively resistant to AD-related cell death. Thus, neuronal populations resisting cell death in AD and hAPP mice can still be drastically altered at the molecular level. The tight link between Aβ-induced cognitive deficits and neuronal depletion of CB and c-Fos suggests an involvement of calcium-dependent pathways in AD-related cognitive decline and could facilitate the preclinical evaluation of novel AD treatments.

Original languageEnglish (US)
Pages (from-to)9572-9577
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number16
DOIs
StatePublished - Aug 5 2003

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Dentate Gyrus
Alzheimer Disease
Calcium
Amyloid beta-Protein Precursor
Proteins
Neurons
Cell Death
Learning
Calbindins
Immediate-Early Genes
Calcium-Binding Proteins
Amyloid Plaques
Amyloid
Transgenic Mice
Brain

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. / Palop, Jorge J.; Jones, Brian; Kekonius, Lisa; Chin, Jeannie; Yu, Gui Qiu; Raber, Jacob; Masliah, Eliezer; Mucke, Lennart.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 16, 05.08.2003, p. 9572-9577.

Research output: Contribution to journalArticle

Palop, Jorge J. ; Jones, Brian ; Kekonius, Lisa ; Chin, Jeannie ; Yu, Gui Qiu ; Raber, Jacob ; Masliah, Eliezer ; Mucke, Lennart. / Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 16. pp. 9572-9577.
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