Short communicationImmunohistochemical study of GABAA receptor α1 subunit in the hippocampal formation of aged brains with Alzheimer-related neuropathologic changes
Introduction
While recent research suggests that some of the pathological changes in Alzheimer's disease (AD) may be due to glutamate-mediated excitotoxicity [17], it is important to bear in mind that much of the adverse effects of glutamate receptor stimulation may be mitigated via the action of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA). It is our hypothesis that neuronal vulnerability in AD is defined in part by a delicate balance of excitatory (i.e., glutamate) and inhibitory (i.e., GABA) input as mediated through selected glutamatergic and GABAergic receptor subtypes. To investigate this hypothesis we examined the anatomical distribution of the α-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA)-sensitive receptor subunits GluR1 and GluR2/3 within the hippocampal formation of subjects with AD 1, 12. These latter studies demonstrated a marked preservation, if not increase, in AMPA receptor immunolabeling within the AD hippocampus, particularly within termination zones of glutamatergic pathways (e.g., molecular layer of dentate gyrus, stratum radiatum of CA3). In addition, as an initial investigation into the GABA system in AD, we examined the distribution and density of the GABAA receptor subunits β2/3 within the AD hippocampus. These studies, like our investigations of AMPA receptor subunits, demonstrated a relative preservation of β2/3 immunoreactivity throughout the hippocampus even in cases with frank neuropathology [15]. Although these latter studies suggest that some subunits of the GABAA receptor are well preserved in the AD hippocampus, it is important to consider that within this structure GABAA receptor subunits display a differential distribution with respect to specific subregions 7, 11, 16, 22, 23and thus may be uniquely affected in AD. Supporting this concept is the knowledge that within the human hippocampus there exists a hierarchy of AD-mediated neuronal vulnerability such that CA1 neurons are more vulnerable than CA2→CA3→DG. Although the mechanism underlying the selected vulnerability of hippocampal neurons is unknown we predict that `vulnerable' vs. `resistant' neurons are unique with respect to their GABA and glutamate receptor phenotypes. To examine this hypothesis, in this study immunocytochemical techniques were employed to examine the distribution of the GABAA receptor α1 subunit within the hippocampus of 19 elderly subjects with Alzheimer-related neuropathologic changes. This study examined the same cases as used previously for studies of β2/3 receptor subunit, thus allowing us to compare directly the results of the two studies. To our knowledge this is the first description of the α1 subunit in the hippocampus of patients with AD.
Section snippets
Subjects
Brain tissue was obtained post mortem from 19 elderly subjects (81.6±7.0 years): six non-demented subjects (82.5±6.9 years) and 13 clinically diagnosed as AD (81.2±7.3 years) (Table 1). The postmortem interval and brain weight of the elderly cases were 3.5±2.3 h and 1132±151 g, respectively. For non-demented subjects, clinical evaluations were largely based on retrospective analysis of medical records and interviews with their physicians or family members. AD subjects were all participants in a
Results
In the mild cases (i.e., Braak stages I and II), the most intense α1 immunolabeling was observed in the molecular layer of the dentate gyrus, CA1 field and subicular complex (i.e., prosubiculum, subiculum proper, presubiculum) (Fig. 1C). In the molecular layer of the dentate gyrus, despite its overall dark appearance, we were able to distinguish between the inner and outer sublayers with the inner being more immunoreactive (Fig. 2A). In addition, in this region a number of darkly-labeled
Discussion
In general, our findings are in agreement with previous studies investigating the distribution of α1 subunits in the dentate gyrus and Ammon's horn of the normal human hippocampal formation 11, 23. In brief, we observed subregional variations in the intensity of α1 immunolabeling. The most intense immunolabeling was observed in the molecular layer of the dentate gyrus and the strata pyramidale and moleculare within CA1 region and subiculum. Notably, this pattern of neuropil labeling was
Acknowledgements
This work was supported by NIH grant AG 08206. Tissue was provided in part by the University of Pittsburgh Alzheimer Disease Research Center funded by the National Institute on Aging AG-05133.
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Current address: Institute of Clinical Medicine, Department of Psychiatry, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba-shi, Ibaraki 305, Japan.