Cited by 248Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCellular transport and secretion

Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation

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Muhammad, Alim, Flores, Ingrid, Zhang, Hong, Yu, Rui, Staniszewski, Agnieszka, Planel, Emmanuel, Herman, Mathieu, Ho, Lingling +6 more·2008·Proceedings of the National Academy of Sciences

Abstract

Although deficiencies in the retromer sorting pathway have been linked to late-onset Alzheimer's disease, whether these deficiencies underlie the disease remains unknown. Here we characterized two genetically modified animal models to test separate but related questions about the effects that retromer deficiency has on the brain. First, testing for cognitive defects, we investigated retromer-deficient mice and found that they develop hippocampal-dependent memory and synaptic dysfunction, which was associated with elevations in endogenous Aβ peptide. Second, testing for neurodegeneration and amyloid deposits, we investigated retromer-deficient flies expressing human wild-type amyloid precursor protein (APP) and human β-site APP-cleaving enzyme (BACE) and found that they develop neuronal loss and human Aβ aggregates. By recapitulating features of the disease, these animal models suggest that retromer deficiency observed in late-onset Alzheimer's disease can contribute to disease pathogenesis.

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Crossref · 10.1073/pnas.0802545105

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Authors
Muhammad, A., Flores, I., Zhang, H., Yu, R., Staniszewski, A., Planel, E., Herman, M., Ho, L., Kreber, R., Honig, L. S., Ganetzky, B., Duff, K., Arancio, O., & Small, S. A.
Affiliations
  • Columbia University Irving Medical Center (US)
  • *Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and
  • University of Wisconsin–Madison (US)
Venue
Proceedings of the National Academy of Sciences
Published
2008-05-20
Volume
105
Issue
20
Pages
7327-7332
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2049746112
Cited by
248
References
39
Citations by year
2026: 6 · 2025: 7 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 17 · 2017: 19 · 2016: 21 · 2015: 19 · 2014: 22 · 2013: 18 · 2012: 19
FWCI
9.03
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 (AG172116, AG025161, R01AG025161, P50AG008702)
  • National Institute of Neurological Disorders and Stroke (NS48447, P01NS048447, R01NS049442, R01NS015390, NS015390, NS049442)
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 › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
retromer complex, Alzheimer's disease, late-onset Alzheimer's disease, hippocampal-dependent memory, synaptic dysfunction, amyloid-beta deposition, amyloid precursor protein, neurodegeneration, neuronal loss, Drosophila model
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Drosophila, Electrophysiology, Heterozygote, Hippocampus, Humans, Models, Biological, Amyloid beta-Peptides, Mice, Knockout, Neurodegenerative Diseases, Mice

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