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Advanced glycation end products (AGE) and the receptor for AGE (RAGE) have been implicated in the chronic complications of diabetes mellitus (DM), and have been reported to play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, we established a polyclonal anti-RAGE antibody, and examined the immunohistochemical localization of amyloid beta protein (Abeta), AGE, and RAGE in neurons and astrocytes from patients with AD and DM. Our anti-RAGE antibody recognized full-length RAGE (50 kd) and N-terminal RAGE (35 kd) in human brain tissue. Abeta-, AGE-, and RAGE-positive granules were identified in the perikaryon of hippocampal neurons (especially from CA3 and CA4) in all subjects. The distribution and staining pattern of these immunopositive granules showed good concordance with each antibody. In AD, most astrocytes contained both AGE-and RAGE-positive granules and their distribution was almost the same. Abeta-positive granules were less common, but Abeta-, AGE-, and RAGE-positive granules were colocalized in one part of a single astrocyte. In DM patients and control cases, AGE-and RAGE-positive astrocytes were very rare. These finding support the hypothesis that glycated Abeta is taken up via RAGE and is degraded through the lysosomal pathway in astrocytes. In addition to the presence of AGE, the process of AGE degradation and receptor-mediated reactions may contribute to neuronal dysfunction and promote the progression of AD.

Advanced glycation end products (AGEs) have been implicated in the chronic complications of diabetes mellitus and have been reported to play an important role in the pathogenesis of Alzheimer's disease. In this study, we examined the immunohistochemical localization of AGEs, amyloid beta protein (A beta), apolipoprotein E (ApoE), and tau protein in senile plaques, neurofibrillary tangles (NFTs), and cerebral amyloid angiopathy (CAA) in Alzheimer's disease and other neurodegenerative diseases (progressive supranuclear palsy, Pick's disease, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex). In most senile plaques (including diffuse plaques) and CAA from Alzheimer's brains, AGE and ApoE were observed together. However, approximately 5% of plaques were AGE positive but A beta negative, and the vessels without CAA often showed AGE immunoreactivity. In Alzheimer's disease, AGEs were mainly present in intracellular NFTs, whereas ApoE was mainly present in extracellular NFTs. Pick's bodies in Pick's disease and granulovacuolar degeneration in various neurodegenerative diseases were also AGE positive. In non-Alzheimer neurodegenerative diseases, senile plaques and NFTs showed similar findings to those in Alzheimer's disease. These results suggest that AGE may contribute to eventual neuronal dysfunction and death as an important factor in the progression of various neurodegenerative diseases, including Alzheimer's disease.

Presenilin-1 (PS-1) has been identified as the protein encoded by the chromosome 14 locus that, when mutated, leads to familial Alzheimer's disease (FAD). The role PS-1 plays in the pathogenesis of Alzheimer's disease (AD) remains unclear. Using a set of antibodies raised against PS-1 synthetic peptides, polyclonal antibody to amyloid beta protein (Abeta) and end-specific antibodies against Abeta40, and Abeta42, immunohistochemical studies were performed on brain sections obtained from AD cases and controls. The PS-1 antibodies clearly stained amyloid angiopathies in AD-affected brains, but no recognizable immunoreactions were observed in any other vessels free from amyloid involvement in either AD-affected brains or controls. Abeta antibodies and the end-specific antibody against Abeta40 also decorated amyloid angiopathies, showing localization similar to that of PS-1. Western blot analyses predominantly detected protein band polypeptide species of a 50 kDa, band, presumably full-length PS-1 protein with N-terminus antisera, since these antibodies turned out to recognize a 50-kDa full-length band in cell lysate of transfected HeLa cell overexpressing PS-1. In addition, we recognized 30, 27 and 25 kDa proteins in both AD and control brain homogenate with these antibodies. In microvessel fractions extracted from brain homogenates, the 50, and 27 kDa fragments were observed in AD-affected brains but not in those of controls. C-terminus rabbit antisera reacted strongly with the 33 and 27 kDa bands, and additionally detected a small amount of full-length PS-1 protein in extracts from AD and control brains. Our present data indicate that PS-1 might be involved in the pathogenesis of amyloid angiopathy in the AD brain.

The localization of amyloid beta protein (A beta), A beta 40, A beta 42, and transthyretin (TTR) was investigated immunohistochemically in the autopsied human kidney, using polyclonal antibodies against TTR, A beta and C-terminal end-specific antibodies against A beta 40 and 42. Immunoreactivities of A beta and A beta 40 were found both in the proximal and distal tubular epithelial cells. But the immunolocalization of A beta 40 was observed predominantly in the distal tubules whereas that of A beta 42 was predominantly recognized in the proximal tubules. TTR, sequestrating protein for A beta, was present in the proximal tubules. The mechanism by which A beta does not form amyloid in Alzheimer's disease outside the brain remains unknown. The tubular epithelial cells in the kidney may provide a useful system to shed light on this issue.

The objective of this study was to assess the pathological role of advanced glycation end products (AGE) and the receptor for AGE (RAGE) in Creutzfeldt-Jakob disease (CJD). We immunohistochemically investigated the occipital lobe of three patients with CJD containing with prion protein (PrP) plaques using anti-AGE and RAGE antibodies. Many PrP-positive plaques were observed in these patients, and the PrP-positive prion plaques also showed immunoreactivity for the anti-AGE antibody. Furthermore, many astrocytes contained-PrP positive granules, and the same astrocytes also contained many AGE- and RAGE-immunopositive granules. The staining pattern of these granules showed good concordance with that of PrP. These findings suggest that there may be a RAGE-mediated PrP degradation pathway in CJD as is the case for beta-amyloid protein in Alzheimer's disease.