Regression stage senile plaques in the natural course of Alzheimer's disease

Resolution process of cerebroparenchymal amyloid beta-protein (A beta) deposition has become of increasing interest in the light of recent advance in the A beta-vaccination therapy for Alzheimer's disease (AD). However, the neuropathological features of degraded and disappearing senile plaque remain poorly characterized, especially in the natural course of the disease. To clarify the natural removal processes of A beta burden in the brain with AD, we devised a triple-step staining method: Bodian for dystrophic neurites, anti-glial fibrillary acidic protein for astrocytes, and anti-A beta. We thus examined 24 autopsied AD brains. A novel form of senile plaques, termed 'remnant plaques', was identified. Remnant plaques were characterized by mesh-like astroglial fibrils within the entire plaque part, A beta deposit debris exhibiting weak A beta immunoreactivity, and only a few slender dystrophic neurites. In remnant plaques, amyloid burden was apparently decreased. The density of remnant plaques increased significantly with disease duration. Dual-labelling immunohistochemistry revealed many A beta-immunoreactive granules in astrocytes and a modest number in microglia, both of which accumulated in senile plaques. We consider amyloid deposits of diffuse and neuritic plaques to be shredded by astrocytic processes from the marginal zone of plaques, and to gradually disintegrate into smaller compartments. Cerebroparenchymal A beta deposits undergo degradation. After a long-standing resolution process, diffuse and neuritic plaques may finally proceed to remnant plaques. Astrocytes are actively engaged in the natural A beta clearance mechanism in advanced stage AD brains, which may provide clues for developing new therapeutic strategies for AD.