Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set
Tóm tắt
Alzheimer's Disease (AD) is the most widespread form of dementia during the later stages of life. If improved therapeutics are not developed, the prevalence of AD will drastically increase in the coming years as the world's population ages. By identifying differences in neuronal gene expression profiles between healthy elderly persons and individuals diagnosed with AD, we may be able to better understand the molecular mechanisms that drive AD pathogenesis, including the formation of amyloid plaques and neurofibrillary tangles. In this study, we expression profiled histopathologically normal cortical neurons collected with laser capture microdissection (LCM) from six anatomically and functionally discrete postmortem brain regions in 34 AD-afflicted individuals, using Affymetrix Human Genome U133 Plus 2.0 microarrays. These regions include the entorhinal cortex, hippocampus, middle temporal gyrus, posterior cingulate cortex, superior frontal gyrus, and primary visual cortex. This study is predicated on previous parallel research on the postmortem brains of the same six regions in 14 healthy elderly individuals, for which LCM neurons were similarly processed for expression analysis. We identified significant regional differential expression in AD brains compared with control brains including expression changes of genes previously implicated in AD pathogenesis, particularly with regard to tangle and plaque formation. Pinpointing the expression of factors that may play a role in AD pathogenesis provides a foundation for future identification of new targets for improved AD therapeutics. We provide this carefully phenotyped, laser capture microdissected intraindividual brain region expression data set to the community as a public resource.
Từ khóa
Tài liệu tham khảo
Angelie E, Bonmartin A, Boudraa A, Gonnaud PM, Mallet JJ, Sappey-Marinier D.Regional differences and metabolic changes in normal aging of the human brain: proton MR spectroscopic imaging study.AJNR Am J Neuroradiol22: 119–127, 2001.
Blesa R, Mohr E, Miletich RS, Hildebrand K, Sampson M, Chase TN.Cerebral metabolic changes in Alzheimer's disease: neurobehavioral patterns.Dementia7: 239–245, 1996.
Bobinski M, de Leon MJ, Convit A, De Santi S, Wegiel J, Tarshish CY, Saint Louis LA, Wisniewski HM.MRI of entorhinal cortex in mild Alzheimer's disease.Lancet353: 38–40, 1999.
de Leon MJ, George AE, Stylopoulos LA, Smith G, Miller DC.Early marker for Alzheimer's disease: the atrophic hippocampus.Lancet2: 672–673, 1989.
Du Y, Ni B, Glinn M, Dodel RC, Bales KR, Zhang Z, Hyslop PA, Paul SM.α2-Macroglobulin as a beta-amyloid peptide-binding plasma protein.J Neurochem69: 299–305, 1997.
Goode N, Hughes K, Woodgett JR, Parker PJ.Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes.J Biol Chem267: 16878–16882, 1992.
Imahori K, Uchida T.Physiology and pathology of tau protein kinases in relation to Alzheimer's disease.J Biochem (Tokyo)121: 179–188, 1997.
Lehericy S, Marjanska M, Mesrob L, Sarazin M, Kinkingnehun S.Magnetic resonance imaging of Alzheimer's disease.Eur Radiol17: 347–362, 2006.
Loessner A, Alavi A, Lewandrowski KU, Mozley D, Souder E, Gur RE.Regional cerebral function determined by FDG-PET in healthy volunteers: normal patterns and changes with age.J Nucl Med36: 1141–1149, 1995.
Mahley RW, Innerarity TL, Rall SC Jr, Weisgraber KH.Plasma lipoproteins: apolipoprotein structure and function.J Lipid Res25: 1277–1294, 1984.
Maiese K, Chong ZZ.Insights into oxidative stress and potential novel therapeutic targets for Alzheimer disease.Restor Neurol Neurosci22: 87–104, 2004.
Mesulam M.Behavioral Neuroanatomy. In:Principles of Behavioral and Cognitive Neurology.Cary, NC: Oxford Univ. Press, 2000, p. 1–120.
Mielke R, Herholz K, Grond M, Kessler J, Heiss WD.Clinical deterioration in probable Alzheimer's disease correlates with progressive metabolic impairment of association areas.Dementia5: 36–41, 1994.
Narita M, Holtzman DM, Schwartz AL, Bu G.Alpha2-macroglobulin complexes with and mediates the endocytosis of beta-amyloid peptide via cell surface low-density lipoprotein receptor-related protein.J Neurochem69: 1904–1911, 1997.
Rapoport SI.Positron emission tomography in Alzheimer's disease in relation to disease pathogenesis: a critical review.Cerebrovasc Brain Metab Rev3: 297–335, 1991.