Glial Vascular Degeneration in CADASIL
| Autor: | Matthew Dong, Suzanne M. de la Monte, Thea Brennan-Krohn, Stephen Correia, Stephen Salloway |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Pathology
medicine.medical_specialty Notch signaling pathway CADASIL Biology Nerve Fibers Myelinated Article White matter Notch 3 medicine Humans Vascular Diseases Notch 1 Aged Glial fibrillary acidic protein Dementia Vascular Gene Expression Profiling General Neuroscience General Medicine Middle Aged medicine.disease SMA Psychiatry and Mental health Clinical Psychology medicine.anatomical_structure Cerebral cortex Nerve Degeneration biology.protein Endothelium Vascular Geriatrics and Gerontology Neuroglia |
| Zdroj: | Journal of Alzheimer's Disease. 21:1393-1402 |
| ISSN: | 1875-8908 1387-2877 |
| Popis: | CADASIL is a genetic vascular dementia caused by mutations in the Notch 3 gene on Chromosome 19. However, little is known about the mechanisms of vascular degeneration. We characterized upstream components of Notch signaling pathways that may be disrupted in CADASIL, by measuring expression of insulin, IGF-1, and IGF-2 receptors, Notch 1, Notch 3, and aspartyl-(asparaginyl)-β-hydroxylase (AAH) in cortex and white matter from 3 CADASIL and 6 control brains. We assessed CADASIL-associated cell loss by measuring mRNA corresponding to neurons, oligodendroglia, and astrocytes, and indices of vascular degeneration by measuring smooth muscle actin (SMA) and endothelin-1 expression in isolated vessels. Immunohistochemical staining was used to assess SMA degeneration. Significant abnormalities, including reduced cerebral white matter mRNA levels of Notch 1, Notch 3, AAH, SMA, IGF receptors, myelin-associated glycoproteins, and glial fibrillary acidic protein, and reduced vascular expression of SMA, IGF receptors, Notch 1, and Notch 3 were detected in CADASIL-lesioned brains. In addition, we found CADASIL-associated reductions in SMA, and increases in ubiquitin immunoreactivity in the media of white matter and meningeal vessels. No abnormalities in gene expression or immunoreactivity were observed in CADASIL cerebral cortex. In conclusion, molecular abnormalities in CADASIL are largely restricted to white matter and white matter vessels, corresponding to the distribution of neuropathological lesions. These preliminary findings suggest that CADASIL is mediated by both glial and vascular degeneration with reduced expression of IGF receptors and AAH, which regulate Notch expression and function. |
| Databáze: | OpenAIRE |
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