GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. The GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1-LPL complex is crucial for generating lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent in capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We document, by NanoSIMS imaging, that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Association between interleukin-1A polymorphism and cerebral amyloid angiopathy-related hemorrhage

Background and Purpose— It has been suggested that the interleukin-1A (IL-1A) allele 2 is a risk factor for Alzheimer’s disease (AD). Because cerebral amyloid angiopathy–related hemorrhage (CAAH) often coexists with AD, we examined the IL-1A polymorphism in CAAH. Methods— In a case-control study, patients with pathologically verified CAAH, AD patients without intracerebral hemorrhage, and neuropathologically normal control subjects were studied. DNA was extracted from brain tissue, and IL-1A was genotyped. Logistic regression was used to examine the IL-1A polymorphism in CAAH patients with and without AD compared with AD and non-AD control subjects. Results— There were 42 patients with CAAH, 232 AD patients, and 167 non-AD control subjects. In age-adjusted analyses, there was no association between possession of IL-1A allele 2 and risk of CAAH compared with AD control subjects (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.45 to 1.97; P=0.87) or non-AD control subjects (OR, 0.94; 95% CI, 0.47 to 1.87; P=0.86). Stratifying for the presence of apolipoprotein E 2 or 4 demonstrated the known increased risk of CAAH from these lipoprotein E alleles. Subgroup analyses demonstrated a nonsignificant excess of the IL-1A 2,2 genotype in patients with CAAH and AD compared with those CAAH patients who did not have histological evidence indicating AD (OR, 2.17; 95% CI, 0.15 to 122.3; P=0.64). Comparisons between CAAH patients with AD and AD control subjects and between CAAH patients without AD and non-AD control subjects did not demonstrate an association between CAAH and possession of either the IL-1A allele 2 or the 2,2 genotype. Conclusions— The IL-1A allele 2 or 2,2 genotype does not appear to be a major risk factor for CAAH