Abstract

The long term goal of this project is to investigate the functions of nicotinic receptor subpopulations in brain, focusing on potential cytoprotective and memory-enhancing actions of alpha7 receptors for the treatment of Alzheimer's disease. Several hypotheses will be tested: 1) alpha7 receptors protect against apoptotic and necrotic neurotoxic insults by sequentially increasing intracellular calcium concentrations, increasing protein kinase C (pkc) translocation, and elevating bcl-2 levels; 2) accumulation of intracellular calcium ions by the alpha7 selective agonist DMXB is mediated through voltage sensitive calcium channels; 3) mixed agonist/antagonist activity at alpha7 receptors interferes with neuroprotection by attenuating receptor-mediated calcium accumulation; 4) DMXB protects axotomized septal cholinergic neurons selectively by a mechanism that involves activation of septal alpha7 receptors; and 5) alpha7 receptor activation is sufficient to improve memory-related behavior in aged animals. These studies use a combination of approaches, including: enzyme-assays, immunoblotting, histochemistry, patch clamp electrophysiology, and morphological analyses. A variety of assays (e.g., calcium-accumulation, PKC activity, bcl-2 immunohistochemistry) will be conducted in the Chemistry Core associated with this grant.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010485-07
Application #
6234381
Study Section
Project Start
1997-08-15
Project End
1998-07-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Florida
Department
Type
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611

  Publications

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; 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
Payne, Andrew J; Kaja, Simon; Koulen, Peter (2015) Regulation of ryanodine receptor-mediated calcium signaling by presenilins. Receptors Clin Investig 2:e449
Kaja, Simon; Payne, Andrew J; Patel, Krupa R et al. (2015) Differential subcellular Ca2+ signaling in a highly specialized subpopulation of astrocytes. Exp Neurol 265:59-68
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

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