Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases

Abstract

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.

Figure 1.

Photomicrographs of serial sections of the hippocampus from an AD brain, immunostained with anti-Aβ (A and D), anti-AGE (B and E), and anti-ApoE (C and F) antibodies. All types of plaques, diffuse plaque (arrowheads, D–F), primitive plaque (arrows, A–C), and classical plaque (arrowheads, A–C) show Aβ, AGE, and ApoE immunoreactivity. G and H: Double-staining studies with anti-Aβ (blue) and anti-AGE (red) antibodies of the hippocampus from an AD brain. G: Representative double staining in a classical plaque. Most senile plaques show both Aβ and AGE immunoreactivity (purple; arrows, H), but some plaques show only AGE immunoreactivity (red; arrowheads, H). Magnification, ×190 (A–C), ×280 (D–F), and ×380 (G and H).

Figure 2.

Serial sections of leptomeningeal vessels (A–C) and parenchymal vessels (D–F) in the temporal lobe of an AD brain. These sections were stained with anti-Aβ (A and D), anti-AGE (B and E), and anti-ApoE (C and F) antibodies. Blood vessels with amyloid angiopathy are labeled by both anti-AGE (B) and anti-ApoE (C). Some blood vessels without amyloid deposits are labeled by both anti-AGE (E) and anti-ApoE (F). Magnification, ×125 (A–C) and ×200 (D–F).

Figure 3.

Photomicrographs of serial sections of the hippocampus from an AD patient (A–C), a patient with Guamanian Parkinson-dementia complex (D–F), and a control subject (G–I). Both I-NFTs (arrows) and E-NFTs (arrowheads) are strongly labeled by anti-tau protein antibody (A, D, and G). I-NFTs show definite AGE immunoreactivity (arrows), whereas E-NFTs are virtually negative (arrowheads, B, E, and H). E-NFTs show strong ApoE immunoreactivity (arrowheads), but I-NFTs are negative (arrows, C, F, and I). Magnification, ×380.

Figure 4.

Serial sections of the temporal lobe from a Pick’s disease brain (A and B). The Pick body reacts with anti-tau protein antibody (A). The same structure is labeled by anti-AGE antibody (B). Serial sections of pyramidal neurons in the hippocampus from an AD brain (C and D). Granulovacuolar degeneration is identified by H&E staining (C). Some granules inside the vacuoles are weakly labeled by anti-AGE antibody (arrows, D), but other granules are not labeled (arrowhead, D). Sections of pyramidal neurons in the hippocampus from AD (E) and Guamanian PDC (F). Many AGE-positive granules were observed in pyramidal neurons. Magnification, ×380.