The aim of this Program Project is to develop reliable, safe, and rational gene transfer procedures to repair or replace neurotransmitter function in relevant animal models of Alzheimer's Disease (AD). Project 1 focuses on the uses of lentivirus to replace age related decline of the cholinergic system in aged rats by over expression of the CHAT gene regionally; protecting against age related cholinergic cell loss; and testing the therapeutic effects of these genes in the mouse by over expressing a human mutated form of APP. Project 4 will use lentivirus to over express Cre recombinase in transgenic mice with the LOX sites surrounding the CHAT, NGF and P75 genes respectively, and will cross mice with homologous knockout of p75 and NGF gene, with mice over expressing a human mutation of the APP gene, to directly determine the interaction between these related genes. Project 5 will test the hypothesis that development of Alzheimer's disease is due to multiple deficits or """"""""stresses"""""""" which lead to pathology. Project 3 will optimize in vivo vectors for gene therapy in primates by comparing AAV and lentivirus for amount, duration and safety of gene expression. In Project 6 recombinant lentiviral vectors expressing mutant PS1 or APP in developing transgenic models of amyloid deposition in the brain, will examine the interactions of these genes in vivo. The Vector Core, will support high recombinant vectors to all projects. The Projects/Cores in this PPG have been chosen for their relevance in addressing these problems and securing a rational approach to gene therapy in AD. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG010435-12
Application #
6535138
Study Section
Special Emphasis Panel (ZAG1-FAS-3 (M2))
Program Officer
Buckholtz, Neil
Project Start
1991-09-30
Project End
2007-08-31
Budget Start
2002-09-30
Budget End
2003-08-31
Support Year
12
Fiscal Year
2002
Total Cost
$1,925,461
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
005436803
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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

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