APOE4 leads to Neurovascular dysfunction is an early change of Alzheimer's disease?

Abstract

Introduction: 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. Whether APOE4 cerebrovascular effects contribute to cognitive impairment remains, however, largely unknown. Methods: A 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. Results: A recent meta-analysis of BBB peameability based on imaging & biochemical cerebrospinal fluid studies indicated that patients with AD have greater increase in BBB peameability compared with neurologically healthy human controls, which has also been confirmed by postmortem brain tissue (for review, see the articles by Zlocovic, & Sergillo et al). Impotantly, postmortem analysis indicated that the BBB breakdown is more pronounced in individuals with AD who carry the APOE4 allele. Astrocyte-derived human apoE2 & apoE3, 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 APOE 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. The vascular defects in APOE4-expressing mice precede neuronal dysfunction & can initiate neurodegenerative changes. 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). There are apoE isoform-specific effects in the Aβ pathway. 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. Discussion: Future studies should explore whether similar early neuroimaging & biochemical markers of BBB disruption are present in humans carrying the apoE4.