![]() ![]() Based on these reports, we hypothesized that TJs are altered by changes in Aβ-triggered cytosolic calcium influx and MMP expression. For example, Aβ increases MMP-9 activity in murine cerebral endothelial cell cultures ( Lee et al., 2003). Also, enhanced intracellular calcium leads to a change of TJs ( Stuart et al., 1996) as well as induces expression of matrix metalloproteases (MMPs) ( Bond et al., 1998). Aβ induces calcium influx in the cells either directly or indirectly ( Kawahara et al., 2000 Kagan et al., 2002). All of these are important clues, suggesting that Aβ may disrupt the TJ of BBB via interaction with RAGE as a specific mediator. The accumulation of Aβ peptides is believed to be an early and causative event in cerebrovascular alterations ( Selkoe, 2001). ![]() We hypothesize that an initial small increase in luminal Aβ can trigger a vicious cycle of BBB damage and efflux of abluminal Aβ to blood vessels in the course of AD pathology. Indeed, increased levels of free Aβ in plasma have been reported in AD patients as well as AD mouse models ( Matsubara et al., 1999 Kawarabayashi et al., 2001). The BBB controls the entry of plasma-derived Aβ into the CNS by RAGE ( Yan et al., 1996 Deane et al., 2003)and clears brain-derived Aβ in the plasma by LRP-1 ( Shibata et al., 2000). Aβ peptide impairs TJ integrity and increases the paracellular permeability in bovine brain capillary endothelial cell cultures ( Strazielle et al., 2000). ZO-1 binds directly to a wide variety of cellular proteins ( Fanning et al., 1998) and orchestrates the formation of TJ complexes. As a component of the TJ, zonula occludin-1 (ZO-1) was initially identified in the BBB ( Watson et al., 1991), and associated with TJ integrity. Tight junctions (TJs) are the most prominent feature of brain endothelium and are responsible for the BBB integrity. The blood-brain barrier (BBB) regulates the transport of various molecules and restricts permeability across brain endothelium ( Hawkins and Davis, 2005). However, the deposition of Aβ aggregates in cerebral blood vessels and the brain is poorly understood, and the mechanisms that underlie the response to changes in permeability are unknown. Changes of cerebral microvasculature have been reported in the brains of AD subjects and are the major event of AD ( Claudio, 1996 Banks et al., 1997 Heyman et al., 1998). This pathway might play an important role in the pathogenesis of AD.Īlzheimer's disease (AD) is characterized by the accumulation of amyloid β-peptide (Aβ) in the CNS and cerebrovascular changes that lead to cerebral amyloid angiopathy (CAA) ( Ellis et al., 1996). We have identified a potential molecular pathway underlying Aβ-RAGE interaction-induced breakage of BBB integrity. Consistent with these in vitro findings, we found disrupted microvessels near Aβ plaque-deposited areas, elevated RAGE expression, and enhanced MMP secretion in microvessels of the brains of 5XFAD mice, an animal model for AD. Neutralizing antibodies against RAGE and inhibitors of calcineurin and MMPs prevented Aβ 1–42-induced changes in ZO-1, suggesting that Aβ-RAGE interactions alter TJ proteins through the Ca 2+-calcineurin pathway. We found that Aβ 1–42 induces enhanced permeability, disruption of zonula occludin-1 (ZO-1) expression in the plasma membrane, and increased intracellular calcium and matrix metalloproteinase (MMP) secretion in cultured endothelial cells. However, molecular mechanisms underlying Aβ-RAGE interaction-induced alterations in the BBB have not been identified. The receptor for advanced glycation end products (RAGE) is known to interact with amyloid β-peptide (Aβ) and mediate Aβ transport across the BBB, contributing to the deposition of Aβ in the brain. ![]() Disrupted intracellular Ca 2+ homeostasis and breakdown of the BBB have been implicated in the pathogenesis of Alzheimer's disease (AD). The blood–brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. ![]()
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