Glial Vascular Degeneration in CADASIL

Article type: Research Article

Authors: Brennan-Krohn, Thea | Salloway, Stephen | Correia, Stephen | Dong, Matthew | de la Monte, Suzanne M.^{; *}

Affiliations: From the Departments of Pathology (Neuropathology), Neurology, Medicine, and Psychiatry and Human Behavior, the Rhode Island Hospital, Butler Hospital, Veterans Affairs Medical Center, and Warren Alpert Medical School of Brown University, Providence, RI, USA

Correspondence: [*] Correspondence to: Dr. Suzanne M. de la Monte, MD, MPH, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: [email protected].

Note: [] Handling Associate Editor: Jack de la Torre

Abstract: 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.

Keywords: Aspartyl-(asparaginyl)-β-hydroxylase, human, Notch, vascular dementia, white matter degeneration

DOI: 10.3233/JAD-2010-100036

Journal: Journal of Alzheimer's Disease, vol. 21, no. 4, pp. 1393-1402, 2010