Cited by 402Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

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

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Palop, Jorge J., Jones, Brian, Kekonius, Lisa, Chin, Jeannie, Yu, Gui-Qiu, Raber, Jacob, Masliah, Eliezer, Mucke, Lennart·2003·Proceedings of the National Academy of Sciences

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.

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Crossref · 10.1073/pnas.1133381100

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Authors
Palop, J. J., Jones, B., Kekonius, L., Chin, J., Yu, G.-Q., Raber, J., Masliah, E., & Mucke, L.
Affiliations
University of California, San Francisco (US)
Venue
Proceedings of the National Academy of Sciences
Published
2003-07-24
Volume
100
Issue
16
Pages
9572-9577
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2003320905
Cited by
402
References
50
Citations by year
2026: 6 · 2025: 11 · 2024: 12 · 2023: 12 · 2022: 17 · 2021: 13 · 2020: 18 · 2019: 11 · 2018: 16 · 2017: 18 · 2016: 22 · 2015: 21 · 2014: 18 · 2013: 22 · 2012: 34
FWCI
8.07
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG-11385, R37AG011385, R01AG011385)
  • National Institute of Neurological Disorders and Stroke (NS41787, NS43945, R01NS041787, R01NS043945)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Alzheimer's disease, amyloid precursor protein, amyloid-beta, calbindin-D28k, c-fos, dentate gyrus granule cells, calcium-binding proteins, cognitive impairment, learning deficits, transgenic mice, amyloid-beta 42, calcium-dependent signaling, preclinical biomarkers
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Amyloid, Animals, Calcium, Female, Heterozygote, Humans, Immunohistochemistry, Male, Mice, Inbred C57BL, Neurons, RNA, Messenger, Blotting, Western, Proto-Oncogene Proteins c-fos, Dentate Gyrus, Reverse Transcriptase Polymerase Chain Reaction, Mice

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