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Vascular basement membrane components and the lesions of Alzheimer's disease: light and electron microscopic analyses
L S Perlmutter1, M A Myers, E Barrón
1Department of Neurology, University of Southern California School of Medicine, Los Angeles 90033.
Abstract:
Alzheimer's disease (AD) is one of several systemic and cerebral diseases that involve the abnormal deposition of fibrillar proteins called amyloids. All amyloids share conformational and staining characteristics, as well as an association with resident tissue macrophages and two extracellular matrix components [heparan sulfate proteoglycan (HSPG) and amyloid P component]. Vascular, glomerular, and Schwann cell basement membrane pathologies have been documented in many forms of amyloidosis, and often amyloid fibrils fuse to and project from the basement membrane in these diseases. The present report demonstrates the vascular basement membrane (VBM) alterations in AD autopsy samples, and details the methodologies used. Electron microscopy reveals the fusion of amyloid fibrils with the VBM and the alteration of the VBM in the absence of amyloid accumulation. Double-labelling and pre-embed immuno-electron microscopy techniques demonstrate the colocalization of amyloid P component and VBM components with amyloid, and also reveal that amyloid P component is not localized to the cerebral VBM. Finally, a novel correlative light/electron microscopy technique demonstrates the association between amyloid P component and cerebral resident tissue macrophages, the microglia. Taken together, these data suggest that the physicochemical processes of amyloid formation, rather than amyloid deposition, may be responsible for VBM pathology.
Insights
Alzheimer's disease involves amyloid protein buildup. This study shows amyloid formation processes, not just deposition, may alter the vascular basement membrane in Alzheimer's disease.
Area of Science:
- Neuropathology
- Biochemistry
- Extracellular Matrix Biology
Background:
- Alzheimer's disease (AD) is characterized by abnormal amyloid protein deposition.
- Amyloids are fibrillar proteins associated with tissue macrophages and extracellular matrix components like heparan sulfate proteoglycan (HSPG) and amyloid P component.
- Basement membrane pathologies are common in various amyloidosis forms.
Purpose of the Study:
- To investigate vascular basement membrane (VBM) alterations in Alzheimer's disease autopsy samples.
- To elucidate the relationship between amyloid fibrils, VBM, and associated proteins.
- To explore the role of amyloid formation processes in VBM pathology.
Main Methods:
- Electron microscopy to examine VBM structure and amyloid fibril interactions.
- Double-labeling and pre-embed immuno-electron microscopy for colocalization studies.
- Correlative light/electron microscopy to identify protein associations with microglia.
Main Results:
- Amyloid fibrils were observed to fuse with the VBM, and VBM alterations occurred even without amyloid accumulation.
- Amyloid P component and VBM components colocalized with amyloid.
- Amyloid P component was not localized to the cerebral VBM but was associated with microglia.
Conclusions:
- Physicochemical processes of amyloid formation, not solely amyloid deposition, may drive VBM pathology in Alzheimer's disease.
- Microglia play a role in the association of amyloid P component in the cerebral VBM.
- Understanding these mechanisms is crucial for Alzheimer's disease research.