Gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter in the mammalian CNS, hyperpolarizes neuronal membranes by opening a C1 channel intrinsic to the GABA A receptor. The proposed studies investigate the anatomical features and expression of selected GABA A receptor subunits (i.e., alpha1, alpha2, alpha3, alpha4, alpha5, beta1-3, gama2) in human hippocampus of non-pathologic mature and aged individuals (30-90 years of age) and those with Alzheimer's disease (AD) pathology. Underlying these studies are investigations of the P.I. and co-investigators demonstrating (I) subunit specific alteration (i.e., alpha1) in the CA1 field and dentate gyrus of aged rats; (ii) GABA A receptor subunit protein and mRNA alterations (i.e., alpha1, beta2, beta3) in the hippocampal formation of aged brains with AD pathology; (iii) time-dependent alterations of GABA A beta2/3 immunoreactivity in the dentate gyrus following perforant pathway lesions. In addition, pharmacological studies have demonstrated altered drug sensitivities, for example, to benzodiazepines, in the elderly. To date, it is not known the extent to which altered drug responses in the elderly may be attributed to emotional or physical disease, over- or undernutrition, use or abuse of other medications, or alterations in the molecular composition of the GABA A receptor. Throughout these studies we will employ immunohistochemical, in situ hybridization, in situ autoradiogaphic, and biochemical techniques in order to study the regional and laminar pattern of GABA A receptor subunit protein and mRNA expression in the hippocampal formation of aging individuals (SPECIFIC AIM 1) and those with varying extent of AD pathology (SPECIFIC AIM 2). It is our hypothesis that selected GABA A receptor subunits will display differential levels of expression and binding within the various regions of the hippocampus. Moreover, brain tissue obtained from elderly patients will not only show altered levels of expression of specific GABA A subunits, but will have a different subunit composition of the GABA A receptor complex compared to controls. In AD, we hypothesize that these receptor subunits will also display altered levels of expression and binding within selected subregions of the hippocampus. In addition, many of these changes will occur during the early phases of the disease (i.e., plastic/compensatory phase) and be unique from those observed during the end stages of the disease (i.e., neurodegenerative phase). A unique aspect of this study is the study of both aging and AD subjects. Notably, a comparison of these two populations of subjects will provide us with the opportunity of differentiating whether alterations in the anatomy of specific GABA A receptor subunits are associated with normal aging or represent a neuropathologic process.
| Gandy, Sam; Zhang, Yun-wu; Ikin, Annat et al. (2007) Alzheimer's presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. J Neurochem 102:619-26 |
