Developing Topics.

Background: Vascular contributions to dementia & Alzheimer's disease are increasing recognized. Recent studies have suggested that blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction, including the early clinical stages of AD. Apolipoprotein E4(APOE4), the major AD susceptibility gene, leads to accelerated blood-brain barrier breakdown & degeneration of brain capillary pericyte that maintain blood-brain barrier integrity. APOE4 is associated with a loss of anti-inflmmatory function and fails to surpress the basal activation of macrophages and microglia.

Method: An screening yielded publcations of which relevant articles were selected after an evaluation of their titles & abstracts. And then full text of these articles was obtained & compared about above respective subjects thoroughly.

Result: Impotantly, postmortem analysis indicated that the BBB breakdown is more pronounced in individuals with AD who carry the APOE4 allele. Astrocyte-derived human apoE4 leads to an age-dependent progressive BBB breakdown by activating a proinflammatory CypA-nuclear factor(NF)- κB-matrix-metalloproteinase-9 pathway(MMP-9) in brain capillary pericytes. The activation of MMP-9 in APOE4 mice leads to enzymatic degradation of the BBB tight junction & basement membrane proteins resulting in BBB breakdown followed by neuronal uptake of multiple blood-derived neurotoxic proteins(e.g., thrombin, fibrin), perivascular deposition of erythrocyte-derived hemosiderin & microvascular & CBF reductions. This leaky blood-born proteins induce increasing neuroinflmmation & oxidative stress. APOE4 promotes upregulation of proinflammatory cytokines, nitric oxide(NO) release and macrophage cell death in vitro. Astrocyte secreated apoE3 & apoE2, but not apoE4, suppress the CypA-NF- κB-MMP-9 pathway in pericytes via the low density lipoprotein receptor related protein1(LRP1). ApoE4 expression is assocated with a significant increase in amyloid plaques in brain at earlier ages compared with apoE3 or apoE2. ApoE4 impairs A β clearance from & across the BBB in animal models & patients at risk for developing AD.

Conclusion: Future studies should explore whether similar early neuroimaging & biochemical markers of BBB disruption and inflammation are present in humans carrying the ApoE4 allele before cognitive decline and/or A β accumulation occur.