This is the second re-submission of the competitive renewal. Accumulation of AB early in AD appears to play an important role in the mechanisms of synaptic damage and neurodegeneration leading to cognitive deficits. During the previous period of funding we focused at developing new models and treatments for AD using lentiviral vectors expressing or blocking AB degrading enzymes such s neprilysin (NEP). NEP might be important for AD also because it?s possible involvement in neuroprotection and as an interface between environment and genetic regulation of synaptic plasticity responses. NEP cleaves bioactive transmitters such as Neuropeptide Y (NPY) resulting in trophic C-terminal fragments (CTFs). In this context, we hypothesize that among other AB-degrading enzymes, NEP might be involved in neuroprotection in APP transgenic (tg) mice by regulating synaptic remodeling and neurogenesis in the hippocampus. The main objective of this collaborative competitive renewal will be to investigate the molecular mechanisms through which interactions between environment and AB-degrading enzymes regulate synaptic regeneration and neurogenesis during aging and in AD. To this end we propose the following:
Aim 1. To determine the AB-independent effects of NEP and other A^-degrading enzymes in synaptic regeneration during aging to murine models.
Aim 2. To investigate the molecular mechanisms through which AB-degrading enzymes regulate synaptic regeneration during aging and in APP tg models of AD.
Aim 3. To investigate the combined effects of physical activity and expression of AB-degrading enzymes on neurogenesis during aging and in APP tg models of AD.
Aim 4. To evaluate the potention therapeutical and neuroprotective effects of NPY fragments in APP tg models of AD. In collaboration with the Cores with will perform studies of synaptic plasticity, neurogenesis and enhanced physical activity in APP tg, NEP, APP and NPY deficient mice, treated with lentiviral vectors expressing AB- degrading enzymes and NPY fragments. Together, these studies might also help in develop new treatments for AD that will have the dual role of reducing accumulation of neurotoxic Ab species and promoting neurogenesis.

Public Health Relevance

Synaptic damage due to the accumulation of toxic AB species, &alterations in neurogenesis are both important in AD. This project investigates the A'P degrading enzyme neprilysin (NEP) as an interface between environment and genetic regulation of synaptic plasticity and neurogenesis in AD models &will help develop treatments for AD that reduce the accumulation of toxic AB species and promote neurogenesis.

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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