Model‐guided microarray implicates the retromer complex in Alzheimer's disease
Abstract
Although, in principle, gene expression profiling is well suited to isolate pathogenic molecules associated with Alzheimer's disease (AD), techniques such as microarray present unique analytic challenges when applied to disorders of the brain. Here, we addressed these challenges by first constructing a spatiotemporal model, predicting a priori how a molecule underlying AD should behave anatomically and over time. Then, guided by the model, we generated gene expression profiles of the entorhinal cortex and the dentate gyrus, harvested from the brains of AD cases and controls covering a broad age span. Among many expression differences, the retromer trafficking molecule VPS35 best conformed to the spatiotemporal model of AD. Western blotting confirmed the abnormality, establishing that VPS35 levels are reduced in brain regions selectively vulnerable to AD. VPS35 is the core molecule of the retromer trafficking complex and further analysis revealed that VPS26, another member of the complex, is also downregulated in AD. Cell culture studies, using small interfering RNAs or expression vectors, showed that VPS35 regulates Aβ peptide levels, establishing the relevance of the retromer complex to AD. Reviewing our findings in the context of recent studies suggests how downregulation of the retromer complex in AD can regulate local levels of Aβ peptide. Ann Neurol 2005;58:909–919
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A microarray study guided by regional vulnerability identified a defect in the retromer complex, which handles endosome-mediated recycling of membrane proteins.
“One particularly powerful approach involved the use of the pattern of regional vulnerability to guide a microarray study that identified a defect in the retromer complex, which is responsible for endosome-mediated recycling of membrane proteins145.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [145]
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- Authors
- Small, S. A., Kent, K., Pierce, A., Leung, C., Kang, M. S., Okada, H., Honig, L., Vonsattel, J., & Kim, T.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Small, Scott A.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2005-11-28
- Volume
- 58
- Issue
- 6
- Pages
- 909-919
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- OpenAlex
- W2053210112
- Semantic Scholar
- cb7cfded946c0690890816182f518b7781bb3d97
- Cited by
- 440
- References
- 64
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 29 · 2023: 33 · 2022: 29 · 2021: 23 · 2020: 35 · 2019: 21 · 2018: 24 · 2017: 21 · 2016: 29 · 2015: 24 · 2014: 23 · 2013: 22 · 2012: 21
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG08702, P01AG007232, AG 07232, P50AG008702)
- National Institute of Neurological Disorders and Stroke (R01NS043467, NS43467)
- 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 › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, retromer complex, VPS35, Vps26, spatio-temporal modeling, gene expression profiling, entorhinal cortex, dentate gyrus, amyloid-beta, protein trafficking
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Humans, Middle Aged, Endopeptidases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Artifacts, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Protein Transport, trans-Golgi Network, Amyloid Precursor Protein Secretases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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