The previous cycle of this program project examined effects of NGF gene transfer on neuronal degeneration in primate models of aging and cholinergic degeneration, leading to two human clinical trials of NGF gene transfer in Alzheimer's disease (AD) and anatomical confirmation of the hypothesis that degenerating neurons in AD exhibit trophic responses to neurotrophic factors. Thus, this program project has led to translation of novel, potential therapies for AD. This renewal will evolve its focus to two new efforts that both retain a focus on gene delivery in primates, and expand the focus to determine whether emerging and intriguing data from rodents in other aspects of this program are relevant to the primate brain. First, we will determine whether the neurotrophic factor brain-derived neurotrophic factor (BDNF) enhances neuronal function and prevents neuronal loss in the primate entorhinal cortex and hippocampus. Second, striking findings from rodent studies in this program project suggest that physical activity influences neuronal structure, neurogenesis and cognition. To determine the relevance of these findings to complex primate systems, we will determine whether physical exercise enhances hippocampal neuronal structure, synaptic markers, neurogenesis and cognition in aged monkeys. These findings could be important in modifying populational risk factors for dementia, and could establish a rationale for activity enhancement in AD.
Aim 1 : Determine whether BDNF gene delivery prevents neuronal degeneration, enhances hippocampal neurogenesis and improves learning and memory in aged primates.
Aim 2 : Determine whether AAV-2 mediated gene delivery is a safe and effective means for long-term BDNF delivery to the entorhinal cortex for future clinical implementation Aim 3: Determine whether physical activity in aged primates enhances cognition, neuronal structure and neurogenesis.

Public Health Relevance

This proposal will study the therapeutic effects of the neurotrophic factor BDNF and physical activity on age related decline in cognitive and neuronal function using a primate model. This research will promote healthy cognitive aging by testing the effects of physical exercise on brain structure and function.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
La Jolla
United States
Zip Code
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