Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2024-04-10 DOI:10.1007/s00401-024-02721-1

Prabesh Bhattarai, Tamil Iniyan Gunasekaran, Michael E. Belloy, Dolly Reyes-Dumeyer, Dörthe Jülich, Hüseyin Tayran, Elanur Yilmaz, Delaney Flaherty, Bengisu Turgutalp, Gauthaman Sukumar, Camille Alba, Elisa Martinez McGrath, Daniel N. Hupalo, Dagmar Bacikova, Yann Le Guen, Rafael Lantigua, Martin Medrano, Diones Rivera, Patricia Recio, Tal Nuriel, Nilüfer Ertekin-Taner, Andrew F. Teich, Dennis W. Dickson, Scott Holley, Michael Greicius, Clifton L. Dalgard, Michael Zody, Richard Mayeux, Caghan Kizil, Badri N. Vardarajan

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引用次数: 0

Abstract

The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.

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纤连蛋白 1 (FN1) 的罕见遗传变异可预防阿尔茨海默病中的 APOEε4

携带 APOEε4 等位基因的人患阿尔茨海默病（AD）的风险明显增加。也存在认知能力健康的老年 APOEε4 携带者，这表明存在抵消 APOEε4 病理效应的细胞机制；然而，这些机制尚不清楚。我们假设，没有痴呆症的 APOEε4 携带者可能携带有基因变异，这些变异可以保护他们免于发展 APOEε4 介导的 AD 病理学。为了验证这一点，我们利用了美国国家老龄化研究所阿尔茨海默病家族研究（NIA-AD FBS）、华盛顿高地/因伍德哥伦比亚老龄化项目（WHICAP）和阿尔茨海默病家族遗传影响研究（EFIGA）队列中的全基因组测序（WGS）数据，发现了仅在未受影响的 APOEε4 携带者中存在的潜在保护性变异。在 70 岁以上未受影响的同源基因携带者中，我们发现了 510 个罕见的编码变异。对携带这些变异的基因进行的通路分析表明，与细胞外基质（ECM）相关的过程显著富集，这表明 ECM 蛋白的功能修饰具有保护作用。我们优先选择了两个在 ECM 相关基因本体术语（FN1 和Ⅵ型胶原蛋白α2 链 (COL6A2)）中具有较高代表性且已知在血脑屏障 (BBB) 上表达的基因进行尸检验证和体内功能研究。一项对 7185 名 APOEε4 同源携带者组成的大型队列进行的独立分析发现，FN1 的 rs140926439 变异对 AD 有保护作用（OR = 0.29；95% CI [0.11，0.78]，P = 0.014），并可将发病年龄推迟 3.37 年（95% CI [0.42，6.32]，P = 0.025）。在AD APOEε4携带者中，BBB的FN1和COL6A2蛋白水平升高。与患有AD的同卵APOEε4携带者相比，认知能力未受影响的同卵APOEε4携带者的脑表达中FN1沉积明显较低，反应性胶质细胞病变也较少，这表明FN1可能是APOEε4介导的AD相关病理和认知能力下降的下游驱动因素。为了验证我们的发现，我们使用了功能缺失（LOF）突变的斑马鱼模型--fn1b是人类FN1的直向同源物。我们发现，纤连蛋白功能缺失突变减少了神经胶质的形成，加强了神经胶质血管的重塑，并增强了微胶质细胞的反应，这表明 FN1 的病理积累可能会影响毒性蛋白的清除，而 FN1 功能缺失突变则会改善这种情况。我们的研究表明，FN1的血管沉积与APOEε4的致病性有关，而FN1的LOF变异可能会降低APOEε4相关的AD风险，这为针对ECM的潜在治疗干预提供了新的线索，从而降低了AD风险。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.