Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits
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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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Beginning at age 2-3 months, J20 mice show cortical plaques and progressive cell loss in the entorhinal cortex and show cognitive decline by 6-7 months of age.
“Beginning at age 2–3 months, these mice show cortical plaques and progressive cell loss in the entorhinal cortex and show cognitive decline by 6–7 months of age10,11.”
From Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease (2009) · cites this paper as [11]
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Self-citation
- 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
- Publisher
- National Academy of Sciences
- Published
- 2003-07-24
- Volume
- 100
- Issue
- 16
- Pages
- 9572-9577
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC170959
- OpenAlex
- W2003320905
- Semantic Scholar
- 3fe8bef104acae70b64a6c2633e742ff80f57784
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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