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Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation
Open accessAbstract
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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“Previous studies have demonstrated that VPS35 deficiency specifically increases β-cleavage of APP, which is primarily thought to be driven by the reduced trafficking of APP away from endosomes, resulting in increased exposure to BACE1 cleavage [135].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [135]
In the citing paper
“VPS26 haploinsufficiency in mice have been shown to elevate amyloidogenic APP processing, Aβ accumulation, and induce synaptic defects (Muhammad, Flores et al. 2008), and pharmacological stabilization of the retromer complex can attenuate amyloidogenic APP processing in primary cultured mouse neurons (Mecozzi, Berman et al. 2014).”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Muhammad, Flores et al. 2008
In the citing paper
“Moreover, VPS26 heterozygote mice show increased levels of endogenous Aβ and impaired LTP (Muhammad et al., 2008).”
From VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology (2011) · cites this paper as Muhammad et al., 2008
In the citing paper
“The involvement of this pathway in Alzheimer disease was experimentally validated146.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [146]
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Metadata
- 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)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-05-20
- Volume
- 105
- Issue
- 20
- Pages
- 7327-7332
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2386077
- 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
- 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 (AG172116, AG025161, R01AG025161, P50AG008702)
- National Institute of Neurological Disorders and Stroke (NS48447, P01NS048447, R01NS049442, R01NS015390, NS015390, NS049442)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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