This is the second re-submission of the competitive renewal. Accumulation of A 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 A degrading enzymes such s neprilysin (NEP). NEP might be important for AD also because its 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 A-degrading enzymes regulate synaptic regeneration and neurogenesis during aging and in AD. To this end we propose the following:
Aim 1. To determine the A-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 A-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 A-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 A-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 A species, &alterations in neurogenesis are both important in AD. This project investigates the Adegrading 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)
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
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

Showing the most recent 10 out of 181 publications