Scholarlink

<p>Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common <i>Transmembrane Protein 106B</i> (<i>TMEM106B</i>) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether <i>TMEM106B</i> alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype (<i>rs3173615)</i>. We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between <i>TMEM106B</i> risk and CTE presence, CTE stage, TDP-43, and dementia in those &lt; = 65 and &gt; 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by <i>TMEM106B</i> genotype. Among donors &gt; 65 years old, the <i>TMEM106B</i> risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183–6.383], <i>p</i> = 0.019), comparable to the effect of playing &gt; 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278–10.422], <i>p</i> = 0.016). In donors &lt; = 65, <i>TMEM106B</i> risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015–23.705], <i>p</i> = 0.002). <i>TMEM106B</i> gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 (<i>p</i>’s &lt; 0.05), and TNF-α was negatively associated with cortical tau (<i>p</i> = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the <i>TMEM106B</i> risk genotype in CTE. Overall, <i>TMEM106B rs3173615</i> is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月20日

查看全文
  • Shahar Hartman,
  • Nurgul Aytan,
  • Raymond Nicks,
  • Samantha Hawkins,
  • Jonathan Cherry,
  • Victor E. Alvarez,
  • Gaoyuan Meng,
  • Yorghos Tripodis,
  • Brett Martin,
  • Joseph Palmisano,
  • Lee E. Goldstein,
  • Douglas I. Katz,
  • Brigid Dwyer,
  • Daniel H. Daneshvar,
  • John F. Crary,
  • Michael Alosco,
  • Weiming Xia,
  • Ann C. McKee,
  • Jesse Mez,
  • Thor D. Stein

摘要

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B (TMEM106B) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype (rs3173615). We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183–6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278–10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015–23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 (p’s < 0.05), and TNF-α was negatively associated with cortical tau (p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.