title: Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer's pathology and APOE genotype.
abstract: Astrocytes contribute to a variety of functions in the brain, including homeostasis, synapse formation, plasticity, and metabolism. Astrocyte dysfunction may disrupt their normal role, including neuronal support, thereby contributing to neurodegenerative pathologies, including Alzheimer's disease (AD). To understand the role of astrocytes in the pathogenesis of age-related disorders, we isolated astrocytes by laser capture microdissection, using glial fibrillary acidic protein (GFAP) as a marker, and characterized the astrocyte transcriptome at different Braak neurofibrillary tangle stages in postmortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) cohort, using microarray analysis. The largest number of significant, differentially expressed genes were identified when the expression profile of astrocytes from isocortical stages of neurofibrillary tangle pathology (Braak stages V-VI) were compared with entorhinal stages (Braak stages I-II). Dysregulation of genes associated with the actin cytoskeleton, proliferation, apoptosis, and ubiquitin-mediated proteolysis occurred at low Braak stages, while altered regulation of intracellular signaling pathways, including insulin, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways were primarily associated with high levels of Alzheimer-type pathology, and occurred at lower Braak stages in individuals with the APOEε4 allele. Our findings implicate astrocyte dysfunction in the pathogenesis of neurodegenerative pathology in the aging brain, and provide a basis for future candidate studies based on specific pathways.
authors.affiliation: Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Julie E
authors.initials: JE
authors.lastname: Simpson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.forename: Rohini
authors.initials: R
authors.lastname: Raman
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Garwood
authors.forename: Catherine
authors.initials: C
authors.lastname: Gelsthorpe
authors.forename: Lynne
authors.initials: L
authors.lastname: Baxter
authors.forename: Gillian
authors.initials: G
authors.lastname: Forster
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Matthews
authors.forename: Carol
authors.initials: C
authors.lastname: Brayne
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D005838:Genotype; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D042282:Microdissection / Q000379:methods; D011180:Postmortem Changes; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D013702:Temporal Lobe / Q000473:pathology*; D059467:Transcriptome / Q000502:physiology*
chemical_list: D000199:Actins; D001057:Apolipoproteins E; D005904:Glial Fibrillary Acidic Protein