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Ultrastructural studies of the cells forming amyloid fibers in classical plaques
H M Wisniewski1, J Wegiel, K C Wang
1Department of Pathological Neurobiology, New York State Institute for Basic Research in Development Disabilities, Staten Island 10314.
Abstract:
Three-dimensional reconstruction and ultrastructural studies of classical plaques from the cortex of patients with Alzheimer's disease showed that microglial cells of the plaques are the amyloid-forming cells. The amyloid star of the single plaque represents the product of five or six microglial cells covering about 80% of the amyloid star surface. The amyloid fibers appear to be formed within altered cisterns of the endoplasmic reticulum. Distended cisterns form channels filled with amyloid fibers. Numerous vesicles derived from the Golgi apparatus appear to be attached to or fused with the amyloid-filled channels. Reconstruction of the amyloid star and the microglia cell pole that forms the amyloid star reveals three different zones of distribution of cytoplasmic organelles and amyloid deposits. The peripheral zone comprises channels filled with loosely packed amyloid fibers arranged in a parallel manner. The transient zone consists of a mixture of fusing amyloid channels and products of disintegration of cytoplasmic pockets, dense bodies and fragments of cellular membranes. The core of the amyloid star is composed of condensed, densely packed amyloid fibers that are free of cellular debris. Formation of the three zones supports the idea that the microglia/macrophages are not phagocytes but instead are the cells manufacturing the amyloid fibers.
Insights
Microglial cells in Alzheimer's disease plaques actively form amyloid fibers, originating within their endoplasmic reticulum. These cells, not phagocytes, are the primary manufacturers of amyloid deposits in the brain.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Alzheimer's disease (AD) is characterized by amyloid plaques in the brain.
- The cellular origin of amyloid-beta (Aβ) within these plaques has been debated.
- Microglial cells are immune cells present in AD lesions.
Purpose of the Study:
- To investigate the cellular source of amyloid fiber formation in Alzheimer's disease plaques.
- To elucidate the ultrastructural mechanisms of amyloid production by microglial cells.
Main Methods:
- Three-dimensional reconstruction of classical plaques from Alzheimer's disease patient cortex.
- Ultrastructural analysis using electron microscopy.
Main Results:
- Microglial cells within plaques were identified as the primary amyloid-forming cells.
- Amyloid fibers originate within altered endoplasmic reticulum cisterns of microglia.
- Distinct zones (peripheral, transient, core) of amyloid deposition and cellular components were observed, suggesting active production rather than phagocytosis.
Conclusions:
- Microglia/macrophages are the cells responsible for manufacturing amyloid fibers in Alzheimer's disease plaques.
- This finding challenges the traditional view of microglia solely as phagocytes in plaque pathology.
- Understanding this mechanism may offer new therapeutic targets for Alzheimer's disease.