👤 Ruud D Fontijn

In Alzheimer's disease (AD) more than 50% of the patients are affected by capillary cerebral amyloid-angiopathy (capCAA), which is characterized by localized hypoxia, neuro-inflammation and loss of blood-brain barrier (BBB) function. Moreover, AD patients with or without capCAA display increased vessel number, indicating a reactivation of the angiogenic program. The molecular mechanism(s) responsible for BBB dysfunction and angiogenesis in capCAA is still unclear, preventing a full understanding of disease pathophysiology. The Liver X receptor (LXR) family, consisting of LXRα and LXRβ, was reported to inhibit angiogenesis and particularly LXRα was shown to secure BBB stability, suggesting a major role in vascular function. In this study, we unravel the regulatory mechanism exerted by LXRα to preserve BBB integrity in human brain endothelial cells (BECs) and investigate its role during pathological conditions. We report that LXRα ensures BECs identity via constitutive inhibition of the transcription factor SNAI2. Accordingly, deletion of brain endothelial LXRα is associated with impaired DLL4-NOTCH signalling, a critical signalling pathway involved in vessel sprouting. A similar response was observed when BECs were exposed to hypoxia, with concomitant LXRα decrease and SNAI2 increase. In support of our cell-based observations, we report a general increase in vascular SNAI2 in the occipital cortex of AD patients with and without capCAA. Importantly, SNAI2 strongly associated with vascular amyloid-beta deposition and angiopoietin-like 4, a marker for hypoxia. In hypoxic capCAA vessels, the expression of LXRα may decrease leading to an increased expression of SNAI2, and consequently BECs de-differentiation and sprouting. Our findings indicate that LXRα is essential for BECs identity, thereby securing BBB stability and preventing aberrant angiogenesis. These results uncover a novel molecular pathway essential for BBB identity and vascular homeostasis providing new insights on the vascular pathology affecting AD patients. Show less

Increasing evidence suggests that vascular dysfunction in the brain is associated with early stages of Alzheimer's disease. Amyloid-β deposition in the microvasculature of the brain, a process referred to as capillary cerebral amyloid angiopathy (capillary CAA), propagates vascular remodelling, which results in impaired function of the blood-brain barrier, reduced cerebral perfusion and increased hypoxia. While improving vascular function may be an attractive new way to fight capillary CAA, the underlying factors that mediate vascular alterations in Alzheimer's disease and capillary CAA pathogenesis remain largely unknown. Here we provide first evidence that angiopoietin like-4 (ANGPTL4), a hypoxia-induced factor, is highly expressed by reactive astrocytes in well characterized post-mortem tissues of patients with capillary CAA. Our in vitro studies reveal that ANGPTL4 is upregulated and secreted by human cortical astrocytes under hypoxic conditions and in turn stimulates endothelial cell migration and sprouting in a 3D spheroid model of human brain endothelial cells. Interestingly, plasma levels of ANGPTL4 are significantly increased in patients with vascular dementia compared to patients with subjective memory complaints. Overall, our data suggest that ANGPTL4 contributes to pathological vascular remodelling in capillary CAA and that detection of ANGPTL4 levels may improve current diagnostics. Ways of counteracting the detrimental effects of ANGPTL4 and thus promoting cerebral vascular function may provide novel treatment regimens to halt the progression of Alzheimer's disease. Show less