BDNF Val66Met Genetic Polymorphism Results in Poor Recovery Following Repeated Mild Traumatic Brain Injury in a Mouse Model and Treatment With AAV-BDNF Improves Outcomes

Abstract

Clinicians have long noticed that some Traumatic Brain Injury (TBI) patients have worse symptoms and take a longer time to recover than others, for reasons unexplained by known factors. Identifying what makes some individuals more susceptible is critical to understanding the underlying mechanisms through which TBI causes deleterious effects. We have sought to determine the effect of a single nucleotide polymorphism (SNP) in Brain-derived neurotrophic factor (BDNF) at amino acid 66 (rs6265) on recovery after TBI. There is controversy from human studies as to whether the BDNF Val66Val or Val66Met allele is the risk factor for worse outcomes after brain trauma. We therefore investigated cellular and behavioral outcomes in genetically engineered mice following repeated mild TBI (rmTBI) using a lateral fluid percussion (LFP) injury model. We found that relative to injured Val66Val carriers, injured Val66Met carriers had a larger inflammation volume and increased levels of neurodegeneration, apoptosis, p-tau, activated microglia, and gliosis in the cortex and/or hippocampus at 1 and/or 21 days post-injury (DPI). We therefore concluded that the Val66Met genetic polymorphism is a risk factor for poor outcomes after rmTBI. In order to determine the mechanism for these differences, we investigated levels of the apoptotic-inducing pro BDNF and survival-inducing mature BDNF isoforms and found that Met carriers had less total BDNF in the cortex and a higher pro/mature ratio of BDNF in the hippocampus. We then developed a personalized approach to treating genetically susceptible individuals by overexpressing wildtype BDNF in injured Val66Met mice using an AAV-BDNF virus. This intervention improved cellular, motor, and cognitive behavior outcomes at 21 DPI and increased levels of mature BDNF and phosphorylation of mature BDNF's receptor trkB. This study lays the groundwork for further investigation into the genetics that play a role in the extent of injury after rmTBI and highlights how personalized therapeutics may be targeted for recovery in susceptible individuals.

APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes

“…It is known that BDNF signaling plays an important role in recovery after injury 38,95 . We have previously shown that treatment with overexpression of BDNF in susceptible BDNF Val66Met mice was able to improve outcomes after rmTBI 39 . This suggests that BDNF may be a potential therapeutic target for APOE4 carriers.…”

“…Immunohistochemistry. To collect tissue for immunohistochemistry, after MRI scans, mice from the first cohort were perfused with 0.9% saline, followed by 4% paraformaldehyde at 1 or 21 days after the final injury as described previously 39 . After perfusion, the brains were cryoprotected with 30% sucrose for at least 3 days.…”

“…Morris water maze test. In order to study spatial memory, the Morris water maze test was done as part of the behavioral battery on the same cohort (#3) of mice as previously described 39 . Mice were acclimated to the paradigm and tested for baseline response using a visible platform test one day prior to the start of the injury paradigm.…”

“…Western blot analysis. The cortex and hippocampus on the side ipsilateral to the injury site were collected from the second cohort of mice at 1 and 21 dpi and flash frozen as previously described 39 . For this assay, four mice per group and condition were analyzed at each timepoint.…”

Association between BDNF rs6265 polymorphisms and postoperative cognitive dysfunction in Chinese Han Population

“…The mutation of G to A results in an amino acid residue shift from valine (Val) to methionine (Met) at codon 66 within the BDNF prodomain, which interferes with a sortilin‐binding site disrupting in the intracellular trafficking and thus affecting the sorting of BDNF into secretory vesicles, resulting in reduction of activity‐dependent secretion (Notaras & Buuse, 2015). The rs6265 polymorphism has been found to be associated with memory performance (Kambeitz et al., 2012), Alzheimer disease (Huang, Huang, Cathcart, Smith, & Poduslo, 2007), Parkinson's disease (D'Souza & Rajkumar, 2019), traumatic brain injury (Giarratana, Teng, & Reddi, 2019), greater severity of CAD and incidence of CVD‐related clinical events (Jiang, Babyak, & Brummett, 2017), acute ischemic stroke (Zhou, Ma, & Fang, 2019), bipolar disorder (Lee, Wang, & Chen, 2016), major depression (Schumacher, Jamra, & Becker, 2005), and schizophrenia (Notaras & Buuse, 2015).…”