Affiliations: [a] Department of Pathology and the Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, 975 NE 10th Street, Biomedical Research Center, Oklahoma City, OK 73104, USA | [b] Department of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa 920-8640, Japan | [c] Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Box 645, KMRB Room 1-9644, Rochester, New York 14642, USA
Correspondence:
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Corresponding author: Paula Grammas, Ph.D., Department of Pathology, University of Oklahoma Health Sciences Center BRC, Room 262, Oklahoma City, OK 73104, USA. Tel.: +1 405 271 3224; Fax: +1 405 271 6437; E-mail: [email protected].
Abstract: Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid β (Aβ) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Aβ. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Aβ levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.
