The aim of this Program Project is to explore influences of genes and the environment on neuronal vulnerability to degeneration in aging and Alzheimer's disease (AD), thereby identifying potential translational therapies for humans with AD. The resubmission of this program project will both build upon progress from the previous period of funding, and explore new evidence that physical activity influences cognitive and cellular features of neural function. Each project focuses on these central themes while examining individual mechanisms and specific models in detail. Project 1 focuses on effects of Neuregulin 1 gene expression on AB load, neuronal structure, neurogenesis and behavior on a background of aging and amyloid mutations in mice. Project 2 tests the hypothesis that genetic approaches to modifying amyloid processing, including overexpression of amyloid-degrading enzymes, can improve neuronal structural, electrophysiology, neurogenesis and behavior in amyloid mutant mice. Project 3 examines the extent to which glutamatergic and nicotinic mechanisms influence amyloid processing, caspace activation, neural structure and neurogenesis. Project 4 tests the hypothesis that BDNF ameliorates neuronal dysfunction and death in primate models of entorhinal/hippocampal degeneration using methods clinically practical in AD, and explores whether augmented physical activity in aged primates improves neuronal structure, cognitive ability and neurogenesis. Core A will coordinate activities and administration of all projects and Cores, and provide statistical support. Core B, the Vector Core, will support the a variety of recombinant vector needs that constitute a common theme in all projects. Core C will provide anatomical and electrophysiological support in evaluating effects of interventions from all projects on neuronal structure, synaptic plasticity, neurogenesis and behavior. The interdependency of resources and skills between Projects/Cores, as well as our past success with this PPG, support the argument that the Program Project is the most efficient and cost-effective way to address these issues.

Public Health Relevance

This research aims to identify causes of Alzheimer's disease and to develop potential new treatments. In addition, we seek to promote healthy cognitive aging by testing the effects of physical exercise on brain structure and function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010435-21
Application #
8662628
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Refolo, Lorenzo
Project Start
1997-04-01
Project End
2015-03-31
Budget Start
2014-04-15
Budget End
2015-03-31
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chen, Zhijiang; Donnelly, Christopher R; Dominguez, Bertha et al. (2017) p75 Is Required for the Establishment of Postnatal Sensory Neuron Diversity by Potentiating Ret Signaling. Cell Rep 21:707-720
Hirai, Maretoshi; Arita, Yoh; McGlade, C Jane et al. (2017) Adaptor proteins NUMB and NUMBL promote cell cycle withdrawal by targeting ERBB2 for degradation. J Clin Invest 127:569-582
Kratter, Ian H; Zahed, Hengameh; Lau, Alice et al. (2016) Serine 421 regulates mutant huntingtin toxicity and clearance in mice. J Clin Invest 126:3585-97
Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous ?-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model. J Neurosci 36:7971-84
Spencer, Brian; Potkar, Rewati; Metcalf, Jeff et al. (2016) Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease. J Biol Chem 291:1905-20
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Wang, Ling; Conner, James M; Nagahara, Alan H et al. (2016) Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets. Proc Natl Acad Sci U S A 113:2750-5
van den Hurk, Mark; Kenis, Gunter; Bardy, Cedric et al. (2016) Transcriptional and epigenetic mechanisms of cellular reprogramming to induced pluripotency. Epigenomics 8:1131-49
Xu, Jiqing; de Winter, Fred; Farrokhi, Catherine et al. (2016) Neuregulin 1 improves cognitive deficits and neuropathology in an Alzheimer's disease model. Sci Rep 6:31692
Biane, Jeremy S; Takashima, Yoshio; Scanziani, Massimo et al. (2016) Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning. Neuron 89:1173-1179

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