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Microglia in diffuse plaques in hereditary cerebral hemorrhage with amyloidosis (Dutch). An immunohistochemical study
M L Maat-Schieman1, A J Rozemuller, S G van Duinen
1Department of Neurology, University Hospital Leiden, The Netherlands.
Abstract:
In hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) beta/A4 amyloid deposition is found in meningocortical blood vessels and in diffuse plaques in the cerebral cortex. Diffuse plaques putatively represent early stages in the formation of senile plaques. Microglia are intimately associated with congophilic plaques in Alzheimer's disease (AD), but microglial involvement in diffuse plaque formation is controversial. Therefore, we studied the relationship between microglia and diffuse plaques in the cerebral cortex of four patients with HCHWA-D using a panel of macrophage/microglia markers (mAbs LCA, LeuM5, LeuM3, LN3, KP1, OKIa, CLB54, Mac1, Ki-M6, AMC30 and the lectin RCA-1). Eight AD patients, one demented Down's syndrome (DS) patient and four non-demented controls were included for comparison. In controls and HCHWA-D patients ramified or "resting" microglia formed a reticular array in cortical gray and subcortical white matter. Microglial cells in or near HCHWA-D diffuse plaques retained their normal regular spacing and ramified morphology. In AD/DS gray matter more microglial cells were stained than in controls and HCHWA-D patients. Intensely immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic plaques. In contrast to the resting microglia, these "activated microglia" strongly expressed class II major histocompatibility complex antigen, HLA-DR, and were AMC30-immunoreactive. These findings support the view that microglia play a role in the formation of congophilic plaques but do not initiate diffuse plaque formation. Another finding in this study is the presence of strong monocyte/macrophage marker immunoreactivity in the wall of cortical congophilic blood vessels in HCHWA-D.
Insights
Microglia are involved in forming amyloid plaques in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D), but do not initiate diffuse plaque formation. Activated microglia cluster in congophilic plaques in AD/DS, unlike in HCHWA-D.
Area of Science:
- Neuroscience
- Neuropathology
- Immunology
Background:
- Hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA-D) involves beta/A4 amyloid deposition in cerebral blood vessels and diffuse plaques.
- The role of microglia in diffuse plaque formation, particularly in HCHWA-D, is debated, contrasting with their known association with congophilic plaques in Alzheimer's disease (AD).
Purpose of the Study:
- To investigate the relationship between microglia and diffuse plaques in the cerebral cortex of HCHWA-D patients.
- To compare microglial involvement in diffuse plaque formation in HCHWA-D with congophilic plaque formation in AD and Down's syndrome (DS).
Main Methods:
- Utilized a panel of macrophage/microglia markers (mAbs LCA, LeuM5, LeuM3, LN3, KP1, OKIa, CLB54, Mac1, Ki-M6, AMC30, and RCA-1) to study brain tissue.
- Examined cortical tissue from four HCHWA-D patients, eight AD patients, one DS patient, and four non-demented controls.
Main Results:
- In HCHWA-D and controls, microglia exhibited a resting, ramified morphology and maintained regular spacing, even near diffuse plaques.
- In contrast, AD/DS brains showed increased microglial cell staining, with "activated microglia" (enlarged, expressing HLA-DR and AMC30) clustering in congophilic plaques.
- Monocyte/macrophage marker immunoreactivity was also prominent in the walls of congophilic blood vessels in HCHWA-D.
Conclusions:
- Microglia contribute to the formation of congophilic plaques but do not initiate the formation of diffuse plaques.
- The findings differentiate microglial roles in early (diffuse) versus later (congophilic) amyloid plaque stages.
- HCHWA-D exhibits distinct vascular amyloid deposition with associated monocyte/macrophage markers, differing from microglial involvement in AD plaque pathology.