TY - JOUR
T1 - Model-guided microarray implicates the retromer complex in Alzheimer's disease
AU - Small, Scott A.
AU - Kent, Kelly
AU - Pierce, Aimee
AU - Leung, Conrad
AU - Kang, Min Suk
AU - Okada, Hirokazu
AU - Honig, Lawrence
AU - Vonsattel, Jean Paul
AU - Kim, Tae Wan
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/12
Y1 - 2005/12
N2 - 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.
AB - 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.
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U2 - 10.1002/ana.20667
DO - 10.1002/ana.20667
M3 - Article
C2 - 16315276
AN - SCOPUS:27744576858
SN - 0364-5134
VL - 58
SP - 909
EP - 919
JO - Annals of Neurology
JF - Annals of Neurology
IS - 6
ER -