Alzheimer's disease (AD) is the leading cause for dementia that afflicts more than 4.5 million people in? this country. Various genetic and epigenetic factors are implicated in the etiology of AD, among which aging? is the single most significant factor.? Cyclin dependent kinase 5 (Cdk5) is a small protein Ser/Thr kinase. When associated with its regulatory? activator p35 or p39, Cdk5 plays an essential role in neuronal positioning, axon guidance, and synaptic? plasticity. Under neurotoxic conditions, p35 is cleaved by calpain to become p25, which encompasses the? carboxyl-terminal two thirds of p35. p25 is more stable and displays an altered subcellular localization from? p35. These properties of p25 cause aberrant activation of Cdk5. We created an inducible p25 transgenic? mouse model (CK-p25) that manifests profound neurodegeneration, neurofibrillary tangle pathology, and? elevated Abeta peptides in the cortex and hippocampus. These observations indicate that elevation of p25? alone can cause AD-like pathology.? Recently, we examined the transcriptional profile of the CK-p25 mice by microarray analyses.? Remarkably, a total of 82 genes known to be involved in DNA repair/replication and/or cell cycle progression? are dramatically upregulated in 2-week induced CK-p25 mice. Genes include a number of well known DNA? damage response genes such as Rad51, nuclear protein 95, and uracil DNA glycosylase, some of which? were upregulated over 30-fold (Affymetrix expression values). Such an expression profile strongly suggests? DNA damage-induced responses as an early and possibly causative event in p25-mediated? neurodegeneration. p25 may cause DNA damage, and/or play an apical role in the DNA damage response.? The NAD+-dependent deacetylase SIRT1, shown to be an important modulator of lifespan in many? different organisms from yeast to mammals, is upregulated in postmortem AD brain samples and in CK-p25? Tg brains. In addition, in collaboration with Dr. David Sinclair, we found that SIRT1 overexpression or? activation by resrevatrol resulted in protection against neurotoxicity in p25 expressing neurons. SIRT1 has? been shown to modify chromatin and its yeast homologue, Sir2, functions to maintain genomic stability.? Thus, it is possible that SIRT1 represses p25-mediated DNA damage and that this activity accounts for the? neuroprotective activity of SIRT1.? We will collaborate with Drs. Bruce Yankner, David Sinclair, and Junying Yuan to test the hypothesis that? DNA damage response elicited by the p25/Cdk5 kinase plays an important role in neurodegeneration. We? will also determine the role of SIRT1 in ameliorating neurodegeneration and the DNA damage response? induced by p25.

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Kim, Jeongkyu; Sturgill, David; Tran, Andy D et al. (2016) Controlled DNA double-strand break induction in mice reveals post-damage transcriptome stability. Nucleic Acids Res 44:e64
Gomes, Ana P; Sinclair, David A (2015) Measuring PGC-1? and its acetylation status in mouse primary myotubes. Methods Mol Biol 1241:49-57
Ofengeim, Dimitry; Ito, Yasushi; Najafov, Ayaz et al. (2015) Activation of necroptosis in multiple sclerosis. Cell Rep 10:1836-49
Lu, Tao; Aron, Liviu; Zullo, Joseph et al. (2014) REST and stress resistance in ageing and Alzheimer's disease. Nature 507:448-54
Hubbard, Basil P; Gomes, Ana P; Dai, Han et al. (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339:1216-9
Gräff, Johannes; Kahn, Martin; Samiei, Alireza et al. (2013) A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J Neurosci 33:8951-60
Hubbard, Basil P; Sinclair, David A (2013) Measurement of sirtuin enzyme activity using a substrate-agnostic fluorometric nicotinamide assay. Methods Mol Biol 1077:167-77
Gabuzda, Dana; Yankner, Bruce A (2013) Physiology: Inflammation links ageing to the brain. Nature 497:197-8
Armour, Sean M; Bennett, Eric J; Braun, Craig R et al. (2013) A high-confidence interaction map identifies SIRT1 as a mediator of acetylation of USP22 and the SAGA coactivator complex. Mol Cell Biol 33:1487-502
Sinclair, David A (2013) Studying the replicative life span of yeast cells. Methods Mol Biol 1048:49-63

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