Converging Perturbed Microvasculature and Microglial Clusters Characterize Alzheimer Disease Brain

N.      Jantaratnotai; C.      Schwab; J.      K. Ryu; P.      L. McGeer; J.      G. McLarnon

Abstract

We have investigated physical properties of microvasculature and vessel association with microglial clusters in cortical tissue from Alzheimer disease individuals, classified as severe (ADsev) or mild (ADmild), and nondemented controls (ND). Immunostaining with laminin or von Willebrand factor demonstrated numbers of microvessels and microvascular density were significantly higher in ADsev cases compared with levels in ADmild or ND cases suggesting proangiogenic activity in ADsev brain. Evidence for extravascular laminin immunoreactivity was found in ADsev tissue and was largely absent in ADmild and ND cases suggesting vascular remodeling in ADsev brain included abnormalities in blood vessels. Microgliosis was progressively increased from ND to ADmild to ADsev with the latter demonstrating areas of clustered microglia (groupings of three or more cells) rarely observed in ADmild or ND cases. Microglial clusters in ADsev brain were in close proximity with extravascular laminin and also plasma protein, fibrinogen, implicating vascular perturbation as a component of inflammatory reactivity. ADsev brain also exhibited elevated levels of the proinflammatory/ angiogenic factors tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) in association, relative to non-association, with microglial clusters. The presence of extravascular laminin and fibrinogen and the vascular modifying factors, TNF-α and VEGF in localization with clusters of activated microglia, is consistent with microglial- induced vascular remodeling in ADsev brain. Microglial-vascular reciprocal interactions could serve a critical role in the amplification and perpetuation of inflammatory reactivity in AD brain.

Keywords: Alzheimer disease, microglial clusters, perturbed angiogenesis, extravascular laminin and fibrinogen, TNF-α, VEGF, leaky blood brain barrier.

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