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)
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Special Emphasis Panel (ZAG1-ZIJ-6)
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University of California San Diego
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Eleuteri, Simona; Di Giovanni, Saviana; Rockenstein, Edward et al. (2015) Novel therapeutic strategy for neurodegeneration by blocking A? seeding mediated aggregation in models of Alzheimer's disease. Neurobiol Dis 74:144-57
Dhungel, Nripesh; Eleuteri, Simona; Li, Ling-Bo et al. (2015) Parkinson's disease genes VPS35 and EIF4G1 interact genetically and converge on ?-synuclein. Neuron 85:76-87
Blurton-Jones, Mathew; Spencer, Brian; Michael, Sara et al. (2014) Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res Ther 5:46
Vilar, Marçal; Sung, Tsung-Chang; Chen, Zhijiang et al. (2014) Heterodimerization of p45-p75 modulates p75 signaling: structural basis and mechanism of action. PLoS Biol 12:e1001918
Spencer, Brian; Verma, Inder; Desplats, Paula et al. (2014) A neuroprotective brain-penetrating endopeptidase fusion protein ameliorates Alzheimer disease pathology and restores neurogenesis. J Biol Chem 289:17917-31
Overk, Cassia R; Cartier, Anna; Shaked, Gideon et al. (2014) Hippocampal neuronal cells that accumulate ?-synuclein fragments are more vulnerable to A? oligomer toxicity via mGluR5--implications for dementia with Lewy bodies. Mol Neurodegener 9:18
Overk, Cassia R; Masliah, Eliezer (2014) Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease. Biochem Pharmacol 88:508-16
Dubal, Dena B; Yokoyama, Jennifer S; Zhu, Lei et al. (2014) Life extension factor klotho enhances cognition. Cell Rep 7:1065-76
Sekiyama, Kazunari; Waragai, Masaaki; Akatsu, Hiroyasu et al. (2014) Disease-Modifying Effect of Adiponectin in Model of ?-Synucleinopathies. Ann Clin Transl Neurol 1:479-489
Games, Dora; Seubert, Peter; Rockenstein, Edward et al. (2013) Axonopathy in an ýý-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated ýý-synuclein. Am J Pathol 182:940-53

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