: Synaptic loss and neurodegeneration in the neocortex and limbic system in patients with Alzheimer's disease (AD) results in characteristic cognitive alterations. Therefore, to better understand the pathophysiology of AD it is necessary to understand the cellular and molecular mechanisms involved in synaptic damage. During the course of funding for this project the applicants have shown that abnormal functioning of amyloid precursor protein (APP) at the synaptic site might be involved in mechanisms of neurodegeneration in AD. For the renewal period, they hypothesize that abnormal APP functioning might result in deficient functioning of glutamate transporters (GT) which in turn results in increased levels of glutamate at the synaptic cleft and exitotoxicity/neurogeneration. Furthermore, they hypothesize that low density lipoprotein receptor-related protein (LRP) plays an important role in mediating the effects of APP on the GT. Therefore, the main objectives of this revised version of the project are to 1) characterize in vivo the specifity of interactions between APP and GT; 2) assess the in vivo role of putative receptors of APP in mediating the effects of APP on GTs; 3) determine the subcellular mechanisms mediating the effects of APP on GT; 4) determine if altered GT activity, promoted by APP, plays a role in neuroprotection and neurodegeneration. To achieve these aims, levels of mRNA and protein expression and activity (Kd, Bmax) for neuronal and glial GTs will be assessed in the nervous system of challenged (kainic acid injection) and naive NSE-APP transgenic, APP- and LRP-deficient mice by RNAse protection assay, immunochemistry, and competitive and saturated uptake binding assays with D-and L- aspartate. Neuronal and synaptic integrity will be evaluated by immunoquantification of synaptophysin (SYN, synaptic marker) and microtubule associated protein 2 (MAP2, dendritic marker). Additional studies of the role of APP effect on GTs will be performed in a human neuronal cell line (HNT) after treatment with APP, LRP blockers, protein kinase C (PKC) inhibitors and stimulators, and calcium channel blockers. They hypothesize that APP binding to LRP triggers, in addition to the internalization of the ligand, the activation of PKC, which in turn results in GT activity regulation. In this context, they propose to study the role of APP and LRP interactions in regulating the levels of excitotoxins at the synaptic site and to determine how dysfunction of this process might result in neurodegeneration. These studies will help to better understand the mechanisms of synaptic pathology in AD and to develop potential neuroprotective agents that will operate by enhancing the GT activity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG010689-08
Application #
6328610
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Snyder, D Stephen
Project Start
1991-09-29
Project End
2002-11-30
Budget Start
2000-12-15
Budget End
2002-11-30
Support Year
8
Fiscal Year
2001
Total Cost
$169,391
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Jolivalt, C G; Calcutt, N A; Masliah, E (2012) Similar pattern of peripheral neuropathy in mouse models of type 1 diabetes and Alzheimer's disease. Neuroscience 202:405-12
Kragh, Christine Lund; Ubhi, Kiren; Wyss-Coray, Tony et al. (2012) Autophagy in dementias. Brain Pathol 22:99-109
Marr, Robert A; Guan, Hanjun; Rockenstein, Edward et al. (2004) Neprilysin regulates amyloid Beta peptide levels. J Mol Neurosci 22:5-11
Marr, Robert A; Rockenstein, Edward; Mukherjee, Atish et al. (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice. J Neurosci 23:1992-6
Hashimoto, Makoto; Takenouchi, Takato; Rockenstein, Edward et al. (2003) Alpha-synuclein up-regulates expression of caveolin-1 and down-regulates extracellular signal-regulated kinase activity in B103 neuroblastoma cells: role in the pathogenesis of Parkinson's disease. J Neurochem 85:1468-79
Hashimoto, Makoto; Rockenstein, Edward; Masliah, Eliezer (2003) Transgenic models of alpha-synuclein pathology: past, present, and future. Ann N Y Acad Sci 991:171-88
Masliah, Eliezer; Hashimoto, Makoto (2002) Development of new treatments for Parkinson's disease in transgenic animal models: a role for beta-synuclein. Neurotoxicology 23:461-8
Van Uden, Emily; Mallory, Margaret; Veinbergs, Isaac et al. (2002) Increased extracellular amyloid deposition and neurodegeneration in human amyloid precursor protein transgenic mice deficient in receptor-associated protein. J Neurosci 22:9298-304
Hashimoto, Makoto; Hsu, Leigh J; Rockenstein, Edward et al. (2002) alpha-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. J Biol Chem 277:11465-72
Ho, Gilbert J; Hansen, Lawrence A; Alford, Michael F et al. (2002) Age at onset is associated with disease severity in Lewy body variant and Alzheimer's disease. Neuroreport 13:1825-8

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