Vascular signaling abnormalities in Alzheimer disease

Abstract

Our laboratory has documented that brain microvessels derived from patients with Alzheimer disease (AD) express or release a myriad of factors that have been implicated in vascular activation and angiogenesis. In addition, we have documented that signaling cascades associated with vascular activation and angiogenesis are upregulated in AD-derived brain microvessels. These results are consistent with emerging data suggesting that factors and processes characteristic of vascular activation and angiogenesis are found in the AD brain. Despite increases in proangiogenic factors and signals in the AD brain, however, evidence for increased vascularity in AD is lacking. Cerebral hypoperfusion/hypoxia, a potent stimulus for vascular activation and angiogenesis, triggers hypometabolic, cognitive, and degenerative changes in the brain. In our working model, hypoxia stimulates the angiogenic process; yet, there is no new vessel growth. Therefore, there are no feedback signals to shut off vascular activation, and endothelial cells become irreversibly activated. This activation results in release of a large number of proteases, inflammatory proteins, and other gene products with biologic activity that can injure or kill neurons. Pathologic activation of brain vasculature may contribute noxious mediators that lead to neuronal injury and disease processes in AD brains. This concept is supported by preliminary experiments in our laboratory, which show that pharmacologic blockade of vascular activation improves cognitive function in an animal model of AD. Thus, "vascular activation" could be a novel, unexplored therapeutic target in AD.

Developmental and pathological angiogenesis in the central nervous system

“…Decreased vascularity in the brain leads to hypoxia, which in turn stimulates the upregulation of proangiogenic factors and endothelial activation [158]. In a transgenic mouse model of AD, endothelial cell activation occurs in an age-dependent manner and is associated with Aβ deposition [159].…”

“…Activated endothelial cells elaborate a number of proteases, inflammatory factors, and other products with biologic activity that may promote neuronal death (Fig. 4) [158]. …”

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

“…A substantial amount of information on factors whose expression and/or secretion is altered in the BBB in AD has been elucidated by Grammas et al 175 (for review, see ref. 175). Of these secreted products, some were found to be neurotoxic (e.g., thrombin) and others neuroprotective (endothelin-1, and CCL5/RANTES).…”

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…Microvessels isolated from the brain of AD patients express a large number of angiogenic proteins, including VEGF [164], but without evidence of vascular growth [173]. The lack of vascular response could cause a chronic state of activation of endothelial cells [174], resulting in the release of proinflammatory and potentially neurotoxic products.…”