Research reportImmunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease
Introduction
Glucose and other reducing sugars react nonenzymatically with protein amino groups to initiate a posttranslational modification process known as nonenzymatic glycosylation [4], [10], [16]. This reaction proceeds from reversible Schiff bases to stable, covalently bonded Amadori rearrangement products [4]. Once formed, the Amadori products undergo further chemical rearrangement to form irreversibly bound advanced glycation end products (AGE) [4], [16], which are considered to play an important role in the pathogenesis of the chronic complications of diabetes mellitus (DM) [1], [2]. After several components of receptor for AGE (RAGE) were characterized [17], it was also shown that RAGE and AGE play an important role in diabetic nephropathy and atherosclerotic vasculopathy [13], [18], [25].
Alzheimer’s disease (AD) is the most common cause of dementia in Western countries and in Japan. Pathologically, AD is characterized by the presence of senile plaques (SPs), neurofibrillary tangles (NFTs), and sever gliosis. AGE can be identified immunohistochemically in both SPs and NFTs [20], [21]. Furthermore, RAGE is expressed by neurons, microglial cells, and astrocytes in the normal human brain [3], [11], while its expression by cortical neurons increases and becomes more widespread in AD [27]. Since it was reported that RAGE may be the nerve cell receptor for amyloid β protein (Aβ), the role of RAGE in the pathogenesis of AD has attracted considerable attention [6], [11], [28].
We have previous studied the distribution of AGE in AD and several neurodegenerative diseases, and have suggested that AGE may be an important factor in the progression of various neurodegenerative disorders [20]. However, little is known about the detailed role of RAGE in AD [28].
To investigate the role of RAGE in AD and DM, we established an anti-RAGE antibody and performed immunohistochemical studies. Our data demonstrated that RAGE was present in astrocytes from AD brains along with AGE and Aβ, suggesting that RAGE-mediated degradation of Aβ occurs in astrocytes.
Section snippets
Subjects and specimens
Brain tissue specimens were obtained from five pathologically verified cases of AD, three cases of DM, and three age-matched controls. Histological sections were prepared from the cerebral cortex (temporal and parietal lobes) and the hippocampus. None of AD patients or controls had diabetes. The clinical features of the subjects are summarized in Table 1.
Antibodies
A rabbit anti-AGE-modified ribonuclease antibody was used, which has been described previously [14]. This antibody detects AGE formed in vivo,
Western blot analysis
Immunoblotting was performed to confirm specificity for RAGE. It demonstrated three major bands at approximately 35 kd, 50 kd, and 60 kd both in human brain (Fig. 1, lane 1) and in bovine lung extract (Fig. 1, lane 4). Fig. 1, lanes 2 and 5 shows the result of an absorption test. The reaction was disappeared by the preincubation of the antibody with the synthesized peptides in human brain (Fig. 1, lane 2) and bovine lung extract (Fig. 1, lane 5). No immunoreaction was detected with non-immune
Discussion
We characterized a new anti-RAGE antibody by Western blot analysis. The bands at approximately 50 kd, observed in both brain and lung, is considered to be full length RAGE [3], while the 35 kd band is considered to be the NH2-terminal two-thirds of the molecule [3]. Furthermore, absorption tests in Western blot analysis and immunohistochemical staining showed this antibody has an antigenicity against RAGE 167–180 residues. These findings indicate that this anti-RAGE antibody certainly
Acknowledgements
These studies were supported in part of by Grant-in-Aid for Scientific Research (#09470204) to Zenji Makita from the Japanese Ministry of Education, Science, Sports, and Culture, and by a Health Science Research Grants (#H10-Chozyu-033) to Zenji Makita from the Japanese Ministry of Health and Welfare.
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