Upregulation and Expression Patterns of the Angiogenic Transcription Factor Ets-1 in Alzheimer's Disease Brain

Article type: Research Article

Authors: Jantaratnotai, Nattinee^a | Ling, Alden^b | Cheng, Jenny^b | Schwab, Claudia^c | McGeer, Patrick L.^c | McLarnon, James G.^{b; *}

Affiliations: [a] Department of Pharmacology, Faculty of Science, Mahidol University, Phayathai, Bangkok, Thailand | [b] Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada | [c] Kinsmen Laboratory of Neurological Research, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

Correspondence: [*] Correspondence to: Dr. James G. McLarnon, Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Tel.: +1 604 822 5719; Fax: +1 604 822 6012; E-mail: [email protected].

Abstract: Immunohistochemical staining has been used to determine expression patterns of the angiogenic transcription factor, Ets-1, in the brains of Alzheimer's disease (AD) individuals. Brain tissue from non-demented controls showed little expression of Ets-1 whereas in AD brain tissue, Ets-1 was ubiquitously expressed in cortex and hippocampus. Double immunostaining with von Willerbrand factor demonstrated prominent Ets-1 intravascular immunoreactivity (ir) in AD cortical microvessels. In addition, Ets-1 also exhibited extravascular expression characterized by a diffuse pattern of Ets-1 ir in AD brain. Double staining also showed Ets-1 colocalization in microvasculature with the potent angiogenic agent, vascular endothelial growth factor (VEGF). Cell-associated tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine with pro-angiogenic activity, was primarily associated with diffuse extravascular Ets-1 ir. Clusters of HLA-DR positive microglia, resident immune cells of brain which release TNF-α, were also localized with diffuse Ets-1. Intravascular Ets-1 ir was maximally co-localized with soluble amyloid-β peptide (Aβ), Aβ1-40, in microvasculature whereas diffuse extravascular Ets-1 ir appeared in proximity to Aβ plaques in brain parenchyma. Similar overall results were obtained for patterns of Ets-1 staining in AD hippocampal tissue. This work provides novel findings on expression of the angiogenic transcription factor, Ets-1, in vascular remodeling and its association with pro-angiogenic factors, reactive microglia, and Aβ deposition in AD brain.

Keywords: Alzheimer's disease, amyloid-β, angiogenesis, Ets-1, microglia, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF)

DOI: 10.3233/JAD-122191

Journal: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 367-377, 2013