Differential preservation of AMPA receptor subunits in the hippocampi of Alzheimer's disease patients according to Braak stage.

The Alzheimer's disease (AD) brain, characterized pathologically by the presence of senile plaques and neurofibrillary tangles, contains regions that are differentially prone toward development of AD pathology. Within these "vulnerable" regions, specific cell populations appear to be selectively affected; the pyramidal cells of the hippocampal subiculum subfield constitute such a vulnerable region. This study investigated whether the AMPA receptor subunit content (GluR1, GluR2, GluR2/3) within "vulnerable" vs. "resistant" sectors of the hippocampus is quantitatively altered with increasing AD neuropathology, as determined by Braak staging. We hypothesize that the glutamate-mediated vulnerability is highly influenced by the repertoire of glutamate receptors expressed on hippocampal neurons. Our results indicate that AMPA receptor subunit proteins are relatively spared across all Braak stages in resistant subfields (CA2/CA3/Dentate Gyrus). However, within vulnerable sectors, i.e., subiculum, GluR2, and GluR2/3 protein levels decreased 63.77% and 60.60%, respectively, in association with Braak stages I-II and stages III-IV, respectively. In Braak stages V-VI, GluR2 and GluR2/3 protein levels were similar to those of Braak stages I-II. In contrast to GluR2 and GluR2/3, GluR1 protein levels were unchanged within vulnerable sectors throughout all stages of the disease. In interpreting these data, it may be relevant to consider that the GluR2 subunit impedes the flow of Ca(+2) through the AMPA receptor ion channel. Thus, we hypothesize that in resistant sectors, the presence of the GluR2 subunit may provide a neuroprotective role by limiting the flow of extracellular Ca(+2), whereas in vulnerable regions, the reduction of GluR2 may contribute to the vulnerability via a mechanism involving an increase in intracellular Ca(+2) and destabilization of intracellular Ca(+2) homeostasis.