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.
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.
|Nagahara, Alan H; Wilson, Bayard R; Ivasyk, Iryna et al. (2018) MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. Gene Ther 25:104-114|
|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|
|Overk, Cassia; Masliah, Eliezer (2017) Perspective on the calcium dyshomeostasis hypothesis in the pathogenesis of selective neuronal degeneration in animal models of Alzheimer's disease. Alzheimers Dement 13:183-185|
|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|
|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|
|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|
|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|
|Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34|
|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|
Showing the most recent 10 out of 183 publications