The goal of the proposed research is to contribute to the elucidation of the molecular mechanism of Alzheimer's disease with a focus on the deficits observed in synaptic transmission, synaptic plasticity and memory and learning in a mouse model of Alzheimer's disease. The mouse model that will be used in the experiments is a mouse engineered to over expressing the human APP protein carrying mutations which are known to cause Alzheimer's disease in humans. We have demonstrated that these mice exhibit deficits in synaptic transmission, synaptic plasticity, and spatial learning. We will also examine the role of neurogenesis and exercise in Alzheimer's disease.
Aim 1 of this proposal is to examine the role of nicotinic receptors in Alzheimer's disease. Behavioral studies have linked the cholinergic system to learning and memory, which is intriguing given the observation that Alzheimer's patients have a deficiency in memory function and cortical nicotinic receptors. The first class of drugs approved for the treatment of Alzheimer's disease, which still today constitutes the best available treatment, are the cholinesterase inhibitors (Tacrine, Donepezil, Rivastigmine, Galantamine), which boost cholinergic function.
Aim 1 of this proposal will be to test the hypothesis that binding of the beta-amyloid fragment (1-42) to the nicotinic receptor alpha 7 leads to the pathology seen in Alzheimer's disease. These experiments may either support or refute the idea that the cholinergic receptor system plays an important role in Alzheimer's disease. Either outcome will provide important information for developing strategies to prevent or reverse Alzheimer's disease.
Aim 2 of this proposal is to test the role of the APP C-terminal caspase cleavage site and its proteolytic products in Alzheimer's disease. We have shown that mice over expressing the mutant human APP protein that causes human Alzheimer's disease exhibit deficits in synaptic transmission, synaptic plasticity and spatial learning. On the other hand, mice expressing the same mutant APP protein but with a deletion of a caspase cleavage site near the APP protein c-terminal are protected from the deficits. These observations predict that APP cterminal proteolytic fragments are causing synaptic damage and this hypothesis will be tested directly.

Public Health Relevance

Our genetic studies will test ideas about the involvement of neurotransmitter receptors, exercise, and neurogenesis in the mechanism of Alzheimer's disease. We will also test the hypothesis that proteolytic cleavage of the APP protein is an essential step in the development of Alzheimer's disease. The results and insights from these studies should make it possible to develop new targets for drug therapy to treat Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010435-19
Application #
8572153
Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (O4))
Project Start
1997-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
19
Fiscal Year
2012
Total Cost
$265,787
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
Biane, Jeremy S; Takashima, Yoshio; Scanziani, Massimo et al. (2016) Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning. Neuron 89:1173-9
Spencer, Brian; Desplats, Paula A; Overk, Cassia R et al. (2016) Reducing Endogenous α-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
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
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
Rockenstein, Edward; Overk, Cassia R; Ubhi, Kiren et al. (2015) A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies. PLoS One 10:e0121570
Goldberg, Natalie R S; Caesar, Jacqueline; Park, Ashley et al. (2015) Neural Stem Cells Rescue Cognitive and Motor Dysfunction in a Transgenic Model of Dementia with Lewy Bodies through a BDNF-Dependent Mechanism. Stem Cell Reports 5:791-804
Masliah, Eliezer; Spencer, Brian (2015) Applications of ApoB LDLR-Binding Domain Approach for the Development of CNS-Penetrating Peptides for Alzheimer's Disease. Methods Mol Biol 1324:331-7

Showing the most recent 10 out of 176 publications