VEGF-A-related genetic variants protect against Alzheimer’s disease

Abstract

The Apolipoprotein E ( APOE ) genotype has been shown to be the strongest genetic risk factor for Alzheimer’s disease (AD). Moreover, both the lipolysis-stimulated lipoprotein receptor (LSR) and the vascular endothelial growth factor A (VEGF-A) are involved in the development of AD. The aim of the study was to develop a prediction model for AD including single nucleotide polymorphisms (SNP) of APOE , LSR and VEGF-A-related variants. The population consisted of 323 individuals (143 AD cases and 180 controls). Genotyping was performed for: the APOE common polymorphism (rs429358 and rs7412), two LSR variants (rs34259399 and rs916147) and 10 VEGF-A-related SNPs (rs6921438, rs7043199, rs6993770, rs2375981, rs34528081, rs4782371, rs2639990, rs10761741, rs114694170, rs1740073), previously identified as genetic determinants of VEGF-A levels in GWAS studies. The prediction model included direct and epistatic interaction effects, age and sex and was developed using the elastic net machine learning methodology. An optimal model including the direct effect of the APOE e4 allele, age and eight epistatic interactions between APOE and LSR , APOE and VEGF-A-related variants was developed with an accuracy of 72%. Two epistatic interactions (rs7043199*rs6993770 and rs2375981*rs34528081) were the strongest protective factors against AD together with the absence of ε4 APOE allele. Based on pathway analysis, the involved variants and related genes are implicated in neurological diseases. In conclusion, this study demonstrated links between APOE , LSR and VEGF-A-related variants and the development of AD and proposed a model of nine genetic variants which appears to strongly influence the risk for AD.

VEGF Paradoxically Reduces Cerebral Blood Flow in Alzheimer’s Disease Mice

“…Interestingly, recent evidence suggests mutations of VEGF-A protect against Alzheimer’s disease. 21 Two epistatic interactions, each between VEGF-A related single nucleotide polymorphisms identified in large-scale GWAS studies (143 Alzheimer’s disease cases and 180 controls), were the strongest protective factors against Alzheimer’s disease in the absence of ε4 APOE allele, which remained the most significant genetic predisposition. 21 This study suggests that VEGF-A signaling may play a more significant role than previously indicated in the pathogenesis of Alzheimer’s disease.…”

PolyAMiner-Bulk: A Machine Learning Based Bioinformatics Algorithm to Infer and Decode Alternative Polyadenylation Dynamics from bulk RNA-seq data

“…In contrast, the 3’UTR lengthening DAG set was significantly enriched for ErbB, brain-derived neurotrophic factor, circadian rhythm, EGF/EGFR, and insulin signaling pathways (Figure 8D and 8E). Of note, studies have already linked these pathways to AD pathogenesis, but none have looked at these pathways from an APA-centric perspective (67–76). These results lay the preliminary groundwork for future studies to dissect the mechanism by which dysregulated APA drives AD pathobiology.…”

Young serum protects against memory impairment in APP/PS1 transgenic mice by blocking neutrophil infiltration

“…VEGF inhibits CXCL1 via endothelial Cdk5 activity VEGF signaling is markedly reduced in the brain with aging, while increasing VEGF signaling protects against age-related capillary loss, compromised perfusion, and reduced tissue oxygenation 18 , which are also observed in AD patients [47][48][49] . Moreover, VEGF in CSF is associated with longitudinal memory performance, particularly in amyloid and Tau positive individuals 50 , and VEGF-related variants might appear to in uence the risk for AD 51 . Therefore, these reports suggested that VEGF signaling is involved in the development of AD.…”