The goal of this grant is to investigate brain alpha7 nicotinic receptors and their potential as targets for developing drugs for Alzheimer's disease. These receptors have been found to be neuroprotective under a variety of conditions as well as able to improve memory related behaviors in every species evaluated. Recent results also indicate functional interactions between these receptors and amyloid precursor protein (APP) derived peptides. We propose to evaluate these actions of alpha7 nicotinic receptors using GTS-21 and related compounds, which are selective agonists for the receptors. Studies will focus on 3 models: 1) mice that have undergone fimbria-fomix axotomy of the septohippocampal pathway; 2) double transgenic APP/PS1 mice that overexpress Swedish mutant APP695 and mutant presenilin 1 (PS1); and 3) cell cultures expressing alpha7 nicotinic receptors.
Aim 1 determines if activation of intracellular or voltage sensitive calcium channels is necessary for the neuroprotective action of alpha7 nicotinic receptor agonists.
Aim 2 determines whether GTS-21 and a more efficacious alpha7 receptor agonist we developed protect both septal cholinergic and non-cholinergic neurons from axotomy in amyloid-overexpressing APP/PS1 double transgenic mice.
Aim 3 evaluates the effects of GTS-21 on amyloid deposition in the APP/PS1 mouse, based on the observation that chronic nicotine treatment reduces these deposits by 80%. It also evaluates the effects of this drug on memory related deficits in these animals following chronic treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010485-17
Application #
7569460
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
17
Fiscal Year
2008
Total Cost
$346,205
Indirect Cost
Name
University of North Texas
Department
Type
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Richter, Frank; Koulen, Peter; Kaja, Simon (2016) N-Palmitoylethanolamine Prevents the Run-down of Amplitudes in Cortical Spreading Depression Possibly Implicating Proinflammatory Cytokine Release. Sci Rep 6:23481
Means, John C; Gerdes, Bryan C; Kaja, Simon et al. (2016) Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging. Neurochem Res 41:2278-88
Montgomery, Christa L; Keereetaweep, Jantana; Johnson, Heather M et al. (2016) Changes in Retinal N-Acylethanolamines and their Oxylipin Derivatives During the Development of Visual Impairment in a Mouse Model for Glaucoma. Lipids 51:857-66
Kaja, Simon; Payne, Andrew J; Singh, Tulsi et al. (2015) An optimized lactate dehydrogenase release assay for screening of drug candidates in neuroscience. J Pharmacol Toxicol Methods 73:1-6
Sarkar, Saumyendra; Jun, Sujung; Simpkins, James W (2015) Estrogen amelioration of A?-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ER?, AKAP and Drp1. Brain Res 1616:101-11
Kaja, Simon; Payne, Andrew J; Naumchuk, Yuliya et al. (2015) Plate reader-based cell viability assays for glioprotection using primary rat optic nerve head astrocytes. Exp Eye Res 138:159-66
Cheli, V T; Santiago González, D A; Spreuer, V et al. (2015) Voltage-gated Ca2+ entry promotes oligodendrocyte progenitor cell maturation and myelination in vitro. Exp Neurol 265:69-83
Kaja, Simon; Sumien, Nathalie; Shah, Vidhi V et al. (2015) Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels. Mol Neurobiol 52:545-54
Kaja, S; Payne, A J; Nielsen, E Ø et al. (2015) Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels. Neuroscience 304:198-208
Grillo, Stephanie L; Koulen, Peter (2015) Psychophysical testing in rodent models of glaucomatous optic neuropathy. Exp Eye Res 141:154-63

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