Alzheimer's disease (AD) is a neurodegenerative illness that affects nearly 4 million individuals in the USA alone. Understanding of the genetics, biochemistry and pathology of Alzheimer's disease (AD) has advanced in recent years, but the biology of the neurodegeneration remains a mystery. Several AD mouse models have been developed. These near perfect 'genocopies' reproduce some of the pathological features of Alzheimer's disease, but they are imperfect 'phenocopies'. Among other things, they fail to reproduce the phenotype of neuronal cell death. Our lab and others have shown that neurons in populations at-risk for death in the human AD brain present evidence for re-entrance into a cell cycle. We have proposed that this attempt at mitosis is lethal for a neuron and is the proximal cause of the observed neurodegeneration in the human disease. Quantitative analysis of the number of neurons manifesting evidence of cell cycle events (CCEs) predicts a slow death, requiring many months. We now have preliminary evidence that despite the absence of nerve cell death the mouse models do initiate neuronal cell cycles in the appropriate populations. The progression of the disease through the various brain regions mimics the human condition and, significantly, a properly timed 3-month course of NSAID treatment blocks the appearance of the CCEs. In this revised application we propose to complete our description the natural history of the CCEs in 4 different AD mouse models, and to relate them to the other pathological disease markers (amyloid deposition, activated microglia etc.). As part of this aim we will test both hypoxia and immune challenge for their efficacy as a 'second hit' that drives the cycling neurons to die. Second, we will test the response of the CCEs to NSAIDS therapies that are currently being explored for use in the treatment of Alzheimer's disease: ibuprofen, simvastatin and an new approach, GW3965, an agonist of the LXR receptor. We will initiate therapy both before and after the first appearance of the CCEs using different APR transgenes as well as genetic background as variables. The potential value of CCEs as a new outcome measure for use in preclinical AD trials is 5-fold: they are easy to detect; they are a neuronal phenotype; they have a conceptual link to neuronal cell death; they are found in both mouse and man; and they appear early in the disease course. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG024494-01A1
Application #
7103051
Study Section
Special Emphasis Panel (ZRG1-CDIN-D (01))
Program Officer
Snyder, Stephen D
Project Start
2006-09-30
Project End
2011-07-31
Budget Start
2006-09-30
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$342,340
Indirect Cost
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Herrup, Karl; Li, Jiali; Chen, Jianmin (2013) The role of ATM and DNA damage in neurons: upstream and downstream connections. DNA Repair (Amst) 12:600-4
Herrup, Karl (2013) ATM and the epigenetics of the neuronal genome. Mech Ageing Dev 134:434-9
Chen, Jianmin; Herrup, Karl (2012) Glutamine acts as a neuroprotectant against DNA damage, beta-amyloid and H2O2-induced stress. PLoS One 7:e33177
Wilkinson, Brandy L; Cramer, Paige E; Varvel, Nicholas H et al. (2012) Ibuprofen attenuates oxidative damage through NOX2 inhibition in Alzheimer's disease. Neurobiol Aging 33:197.e21-32
Cameron, Brent; Tse, Wayne; Lamb, Raza et al. (2012) Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease. J Neurosci 32:15112-23
Herrup, Karl (2010) Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci 30:16755-62
Herrup, Karl (2010) The involvement of cell cycle events in the pathogenesis of Alzheimer's disease. Alzheimers Res Ther 2:13
Jiao, Xinfu; Chen, Hongxin; Chen, Jianmin et al. (2009) Modulation of neuritogenesis by a protein implicated in X-linked mental retardation. J Neurosci 29:12419-27
Varvel, Nicholas H; Bhaskar, Kiran; Kounnas, Maria Z et al. (2009) NSAIDs prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer disease. J Clin Invest 119:3692-702
Bhaskar, Kiran; Miller, Megan; Chludzinski, Alexandra et al. (2009) The PI3K-Akt-mTOR pathway regulates Abeta oligomer induced neuronal cell cycle events. Mol Neurodegener 4:14

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