Genetic Variant of BDNF (Val66Met) Polymorphism Attenuates Stroke-Induced Angiogenic Responses by Enhancing Anti-Angiogenic Mediator CD36 Expression

Abstract

Brain-derived neurotrophic factor (BDNF) has been shown to be necessary and sufficient for post-stroke recovery in rodents. From these observations, we and others have hypothesized that a common single nucleotide polymorphism (SNP) in the pro-domain of bdnf that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) will affect stroke outcome. Here we investigate the effect of the BDNF genetic variant on ischemic outcome by using mice with a genetic knock-in of the human BDNF variant in both alleles (BDNFMet/Met). Compared with wild-type mice, BDNFMet/Met mice exhibited reduced CNS BDNF levels without a discernable effect on infarct size. Diminished BDNF levels in BDNFMet/Met mice were associated with greater deficits in post-stroke locomotor functions. Additionally, the BDNFMet/Met mice showed reduced angiogenesis and elevated expression of thrombospondin-1 (TSP-1) and its receptor CD36, anti-angiogenic factors. To assess the functional role of CD36 in antagonizing angiogenic response in Met homozygosity at the BDNF locus, we crossed BDNFMet/Met mice with CD36 knock-out mice. The double-mutant mice rescued the angiogenic deficit associated with the BDNFMet/Met mice without alterations in BDNF levels, indicating that the behavioral deficit in BDNFMet/Met mice after stroke is partly related to an unfavorable balance in pro-angiogenic BDNF and anti-angiogenic TSP-1/CD36. The results suggest that CD36 inhibition may be a viable strategy to enhance angiogenesis and possible recovery in human stroke victims who are Met homozygotes at codon 66 of the BDNF locus.

Effects of the BDNF Val66Met Polymorphism on White Matter Microstructure in Healthy Adults

“…Reduced BDNF signaling has been linked to altered differentiation of human fetal and adult oligodendrocyte progenitor cells (Cui et al, 2010) and to regional reductions of myelin-related proteins (Vondran et al, 2010), but these observations would be very difficult to relate to our associations with the Val allele of BDNF, which is the normal functional BNDF allele and has not been associated with reduced BDNF levels in human brain. The animal model literature is consistent in showing that the BDNF Met allele, which alters BDNF protein trafficking and secretion, is associated with reduced BDNF protein levels (Bath et al, 2012;Qin et al, 2011). In humans, the available post-mortem information involves only mRNA, which is not expected to be affected by the Val/Met polymorphisms (eg, http://braincloud.jhmi.edu/) and the results are consistent with this expectation (Colantuoni et al, 2011).…”

Brain derived neurotrophic factor, cardiopulmonary fitness and cognition in patients with coronary artery disease

“…This "neurovascular niche" contributes to functional recovery from stroke (Chopp et al, 2007;Ohab et al, 2006) and possibly to mitigating subtle cognitive deficits resulting from disease of the smaller vessels. Roles of BDNF in the dynamic interactions between neurogenesis (Guo et al, 2008;Louissaint et al, 2002) and angiogenesis (Qin et al, 2011) have been described, but remain to be fully characterized (Kim et al, 2004;Li et al, 2006). The clinical impact of BDNF signaling on cerebrovascular disease has been suggested by greater white matter hyperintensity volumes in carriers of the met BDNF allele 60 years of age or older (Taylor et al, 2008).…”

Inhibition of the CD36 receptor reduces visceral fat accumulation and improves insulin resistance in obese mice carrying the BDNF-Val66Met variant

“…On the other hand, with high affinity toward oxidized lipids and advanced glycation end products, CD36 has been implicated in the development of IR and diabetes (39)(40)(41). We previously reported increased CD36 mRNA levels in the brains of 9 month-old BDNF M/M mice (42). In this study, we observed that BDNF M/M mice fed a HFD develop extreme obesity even at younger ages (i.e., 14-weeks-old), which is accompanied with elevated expression of CD36 in the brain.…”