Microarrays for Alzheimer's Disease Mouse Models

(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.