Cited by 440Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Model‐guided microarray implicates the retromer complex in Alzheimer's disease

Small, Scott A., Kent, Kelly, Pierce, Aimee, Leung, Conrad, Kang, Min Suk, Okada, Hirokazu, Honig, Lawrence, Vonsattel, Jean‐Paul +1 more·2005·Annals of Neurology

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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Crossref · 10.1002/ana.20667

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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.”

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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
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

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