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 referre Show more
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
As a result of the synovial sarcoma associated t(X;18) translocation, the human SYT gene on chromosome 18 is fused to either the SSX1 or the SSX2 gene on the X chromosome. Although preliminary evidenc Show more
As a result of the synovial sarcoma associated t(X;18) translocation, the human SYT gene on chromosome 18 is fused to either the SSX1 or the SSX2 gene on the X chromosome. Although preliminary evidence indicates that the (fusion) proteins encoded by these genes may play a role in transcriptional regulation, little is known about their exact function. We set out to isolate interacting proteins through yeast two hybrid screening of a human cDNA library using SYT as a bait. Of the positive clones isolated, two were found to correspond to the acute leukemia t(10;11) associated AF10 gene, a fusion partner of MLL. Confirmation of these results was obtained via co-immunoprecipitation of endogenous and exogenous, epitope-tagged, SYT and AF10 proteins from cell line extracts and colocalization of epitope-tagged SYT and AF10 proteins in transfected cells. Subsequent sequential mutation analysis revealed a highly specific interaction of N-terminal SYT fragments with C-terminal AF10 fragments. The N-terminal interaction domain of the SYT protein was also found to be present in several SYT orthologs and homologs. The C-terminal interaction domain of AF10 is located outside known functional domains. Based on these results, a model is proposed in which the SYT and AF10 proteins act in concert as bipartite transcription factors. This model has implications for the molecular mechanisms underlying the development of both human synovial sarcomas and acute leukemias. Show less