ArticlesPhenotypic down-regulation of glutamate receptor subunit GluR1 in Alzheimer’s disease☆☆
Introduction
Alzheimer’s disease (AD) is a progressive dementing disorder characterized histologically by the presence of amyloid plaques and neurofibrillary tangles, accompanied by neuronal loss in certain neuronal populations of the brain. In particular, the entorhinal cortex, subiculum, and area CA1 of the hippocampus in AD are severely affected [13], and the neurofibrillary pathology correlates with atrophy of the hippocampal formation [4]. In contrast, the granule cells of the dentate gyrus are generally considered to be spared from the effects of the disease [15]. Whether neuronal loss, solely, accounts for the clinical manifestations of the disease remains a matter of controversy, however.
More than a dozen types of glutamate receptors have been identified by molecular cloning and have been classified into several subfamilies according to their structural homology and pharmacological profiles [14], [33], [44]. Among these, the N-methyl-d-aspartate (NMDA)R1 and GluR1/3 subunits are key subunits that form the physiological receptor complexes of the NMDA-type and α-amino-isoxazolepropionic acid (AMPA)-type channels, respectively [21], [28]. In the brain, amounts and properties of these glutamate receptors are known to be regulated in a plastic manner by various molecules as well as by neuronal activity [35], [36], [37]. Thus, abnormal functioning of these receptors is often implicated in many neurological and psychiatric diseases [2], [9], [23], [26], [27].
Previous autoradiographic studies have demonstrated that levels of AMPA and NMDA binding sites are reduced in the AD hippocampus [7], [19]. Recent immunocytochemical studies have shown that the numbers of GluR1- and GluR2/3-immunolabeled neurons decreased in the whole hippocampus and entorhinal cortex of patients with AD [3], [17]. More detailed immunocytochemistry, however, has revealed that GluR1-like immunoreactivity seems to be increased in the dentate gyrus of patients with AD [17]. Furthermore, such immunohistochemical studies on glutamate receptors had often been performed by using antibodies specific to their carboxyl-termini [31], [41], [42], even though it has been suggested that complete immunohistochemical detection of glutamate receptors seems to be difficult [12], [51] because epitopes on the receptors are often masked by many receptor-associated molecules such as the postsynaptic density proteins [6], [22], [38], [52].
These controversial findings and arguments raise a question of whether true levels of native AMPA receptors in the dentate gyrus increase or decrease with the progression of the disease.
In AD brain tissue the most severe neuronal degeneration was observed in the entorhinal cortex, whereas neuronal population is relatively preserved in the dentate gyrus and primary motor cortical area [13], [15]. Using Western blot analysis under a denatured condition, we therefore investigated the protein concentrations of GluR1 and NMDAR1 receptors in the cerebral neocortex (motor cortex), entorhinal cortex and dentate gyrus of postmortem tissues from patients with AD, and from normal subjects. To confirm the previous histological observations, we also immunostained tissue sections from the hippocampal-entorhinal formation with the same anti-GluR1 antibody. Furthermore, to evaluate contribution of receptor interacting molecules to the GluR1-like immunostaining, we determined the protein levels of a postsynaptic density protein named SAP97, which recognizes and potentially masks the epitope region of GluR1 [24]. Finally, we will discuss the reasons for the divergence of the biochemical and histological results.
Section snippets
Patient selection
Brain tissues were obtained from seven patients with AD (mean age 73.5 ± 10.3 years) and seven nondemented controls (mean age 68.8 ± 12.6 years). The same protein samples were used for the determination of neurotrophin contents in our previous study [34]. These AD patients had clinical histories of dementia; disease duration, 4–18 years; mean, 10.7 years. To further confirm our results, we used an additional set of postmortem samples from AD patients (n = 7; mean age 80.3 ± 7.0; disease
Sampling of the postmortem brains
Postmortem brains were stored at −80°C at the Brain Disease Research Center of Niigata University (Japan) or at the Tokyo Institute of Psychiatry (Japan) (Table 1). For the primary quantitative study, brain tissues were carved from frozen brain slices of seven patients with AD (mean age 73.5 years; range, 57–84 years) and seven nondemented controls (mean age 68.8 years; range, 59–89 years). Neurotrophin contents in the same samples had been determined in our previous study [34]. These AD
Discussion
In the hippocampus, dentate granule cells are known to be resistant to the neurodegeneration that occurs in AD [15], [46]. We found that GluR1 protein levels were decreased significantly in this region of AD patients. In contrast, the levels of a neuronal marker NSE or NMDAR1 were not altered significantly in the dentate gyrus. In the same set of the brain samples, we previously measured the content of BDNF [34], which is most predominantly expressed in the dentate granule cells [18]:
Acknowledgements
We thank Dr. M. Watanabe and Mr. H. Jourdi for valuable suggestions.
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☆ This work was supported by a research grant from the Research Committee for CNS Degenerative Diseases, the Ministry of Health and Welfare, Japan and by the Japan Society for the Promotion of Science (RFTF-96L00203).