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Brain Aging & Gene Expression Patterns Using Microarrays

Cotman, Carl W

30 September 2003 - 31 July 2008
NATIONAL INSTITUTE ON AGING
Total Funding: $ 2,450,598

This project assembles a unique set of brain specimens to test hypotheses on the relationship of inflammation to synaptic regression and neuron death during normal aging and Alzheimer disease (AD) pathogenesis using microarray technology. Because AD risk is driven by aging, we will evaluate normal brains across the adult life span to identify aging changes in gene expression, which may trigger feedforward cascades leading to irreversible neurodegeneration. To carry out this project a consortium of neuroscientists, neuropathologists and clinicians representing 6 ADCs has been assembled. Frozen, unfixed blocks (250 mg/sample) of the entorhinal cortex/subiculum (EC), hippocampus (HPC), superior frontal gyrus (SFG), and sensory-motor cortex (SMC) will be obtained primarily from five well-established NIA ADC brain banks. The tissue blocks will derive from neuropathologically normal controls, MCI, early mild-moderate AD, and terminal moderate-severe AD (N=10/group). PD cases with dementia but without significant AD pathology (N=10/group) will serve as a disease control. Assignment of cases to groups will be based on common ADC antemortem clinical criteria and postmortem neuropathologic criteria, particularly Braak staging. The experimental groups will be matched for gender and postmortem intervals, none of which will exceed 6 hours, a period during which our preliminary studies suggest that relatively little RNA degradation occurs. Total RNA will be characterized for size distribution and analyzed by Affymetrix gene arrays. Data will be stored in a dedicated hard-drive and searched for changes in specific pathways that may be early markers for and underlying causes of AD study. This proposal will focus on two hypotheses: 1). During aging and mild pathology select genes linked to synaptic function show compensatory changes in the initial stages of cognitive decline and these decline as degeneration evolves. 2). Brain inflammation is a key triggering mechanism resulting in conversion to MCI and/or AD and that inflammatory responses follow or precede synaptic change. Once an initial primary paper is published the overall data will be made available to the field via NACC for various investigators to analyze for the testing their own hypotheses.

7 Resulting Publications

• 1.

  2013

  Nicole C Berchtold; Paul D Coleman; David H Cribbs; Joseph Rogers; Daniel L Gillen; Carl W Cotman

  Synaptic genes are extensively downregulated across multiple brain regions in normal human aging and Alzheimer's disease.

  Neurobiology of aging 2013;34(6):1653-61.

• 2.

  2012

  Philip L De Jager; Joshua M Shulman; Lori B Chibnik; Brendan T Keenan; Towfique Raj; Robert S Wilson; Lei Yu; Sue E Leurgans; Dong Tran; Cristin Aubin; et al.

  A genome-wide scan for common variants affecting the rate of age-related cognitive decline.

  Neurobiology of aging 2012;33(5):1017.e1-15.

• 3.

  2012

  David H Cribbs; Nicole C Berchtold; Victoria Perreau; Paul D Coleman; Joseph Rogers; Andrea J Tenner; Carl W Cotman

  Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study.

  Journal of neuroinflammation 2012;9():179.

• 4.

  2011

  Lori B Chibnik; Joshua M Shulman; Sue E Leurgans; Julie A Schneider; Robert S Wilson; Dong Tran; Cristin Aubin; Aron S Buchman; Christopher B Heward; Amanda J Myers; et al.

  CR1 is associated with amyloid plaque burden and age-related cognitive decline.

  Annals of neurology 2011;69(3):560-9.

• 5.

  2010

  Jason J Corneveaux; Winnie S Liang; Eric M Reiman; Jennifer A Webster; Amanda J Myers; Victoria L Zismann; Keta D Joshipura; John V Pearson; Diane Hu-Lince; David W Craig; et al.

  Evidence for an association between KIBRA and late-onset Alzheimer's disease.

  Neurobiology of aging 2010;31(6):901-9.

• 6.

  2008

  Nicole C Berchtold; David H Cribbs; Paul D Coleman; Joseph Rogers; Elizabeth Head; Ronald Kim; Tom Beach; Carol Miller; Juan Troncoso; John Q Trojanowski; et al.

  Gene expression changes in the course of normal brain aging are sexually dimorphic.

  Proceedings of the National Academy of Sciences of the United States of America 2008;105(40):15605-10.

• 7.

  2007

  A Parachikova; M G Agadjanyan; D H Cribbs; M Blurton-Jones; V Perreau; J Rogers; T G Beach; C W Cotman

  Inflammatory changes parallel the early stages of Alzheimer disease.

  Neurobiology of aging 2007;28(12):1821-33.

Scientific Context

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