Microarrays for Alzheimer's Disease Mouse Models

  • Reddy, P (Hemachandra) (PI)

    Project: Research project

    Project Details


    (Revised Abstract) Description: 23. Tools for Research on the Genetics and Proteomics of Aging.
    Alzheimer's disease (AD) is a progressive neurodegenerative disease
    characterized by impairment of cognitive functions and by beta amyloid
    plaques in cerebral cortex and hippocampus. Because of the challenges in
    identifying and obtaining presymptomatic human AD brains, we investigated an
    established amyloid precursor protein (APP) transgenic mice line (Tg2576)
    for gene expression profiles at ages long before (2 months), immediately
    before (5-6 months), and after (18 months) the appearance of amyloid plaque
    pathology and cognitive impairment. We employed cDNA microarray techniques
    and measured mRNA levels of the cerebral cortex in APP transgenic and
    wild-type mice at each time point for 11,400 genes. Our preliminary
    screening of gene expression in APP mice compared to age-matched wild-type
    mice revealed that at 2 months of age, up-regulated genes are associated
    mainly with mitochondrial energy metabolism and oxidative stress, and these
    same genes are progressively up-regulated in 5- and 18-month-old APP mice.
    We confirmed these results by Northern blot and real-time PCR analyses.
    Based on these preliminary results, we hypothesize that impairment of
    mitochondrial energy metabolism is an early cellular event in the
    progression of AD in APP mice. Currently, our laboratory is testing this
    hypothesis by treating APP mice and age-matched wild-type mice with
    mitochondrial antioxidants such as lipoic acid, melatonin and co-enzyme Q10
    to determine whether mitochondrial antioxidants can rescue cognitive
    deficits, reduce mRNA expression, and compensate for biochemical enzymes in
    mitochondrial energy metabolism. Ultimately, successful agents may be used
    as clinical trials in AD patients. However, global screening of gene
    expression for routine detection of gene expression in APP mice after
    treatment with antioxidants is very expensive. To reduce the cost of global
    screening of mouse genes for mRNA expression, we propose to develop custom
    cDNA microarrays for AD transgenic mice. The objective of this research
    proposal is to develop custom cDNA microarrays for AD transgenic mice. In
    the present study, we propose to develop high-sensitivity, low-density
    mitochondrial, oxidative damage and inflammatory response related cDNA
    microarrays in mice. These custom cDNA microarrays will be instrumental in
    continuing our studies on the dysfunction of gene expression before and
    after treatment with mitochondrial antioxidants in APP mice. The outcome of
    this proposed investigation will be useful in screening several
    mitochondrial antioxidants in AD transgenic mouse models as pre-clinical
    trials of AD patients.
    Effective start/end date9/30/039/30/05


    • National Institutes of Health: $75,500.00


    • Medicine(all)


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