Model-guided microarray implicates the retromer complex in Alzheimer's disease.
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 Abeta 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 Abeta peptide.
Small
Scott A
SA
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, and the Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, NY, USA. sas68@columbia.edu
Kent
Kelly
K
Pierce
Aimee
A
Leung
Conrad
C
Kang
Min Suk
MS
Okada
Hirokazu
H
Honig
Lawrence
L
Vonsattel
Jean-Paul
JP
Kim
Tae-Wan
TW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016477:Artifacts; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D021381:Protein Transport / Q000235:genetics; D021601:trans-Golgi Network / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human