遗传上位性调控衰老过程中的淀粉样蛋白沉积。
Genetic epistasis regulates amyloid deposition in resilient aging.
机构信息
Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
出版信息
Alzheimers Dement. 2017 Oct;13(10):1107-1116. doi: 10.1016/j.jalz.2017.01.027. Epub 2017 Mar 17.
INTRODUCTION
The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid β (Aβ) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans.
METHODS
We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative.
RESULTS
We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1-BDNF interactions also significantly influenced Aβ load as measured with [F]Florbetapir positron emission tomography.
DISCUSSION
Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.
简介
脑源性神经营养因子（BDNF）与重要的阿尔茨海默病（AD）遗传风险因素相互作用。具体来说，SORL1 基因内的变异决定了 BDNF 在体外降低淀粉样蛋白β（Aβ）的能力。我们试图测试功能性 BDNF 变异是否与 SORL1 基因型相互作用，以影响人类的表达和下游 AD 相关过程。
方法
我们分析了来自宗教秩序研究/记忆与衰老项目的 441 名受试者的死后大脑 RNA 测序和神经病理学数据，以及来自阿尔茨海默病神经影像学倡议的 1285 名受试者的分子和结构神经影像学数据。
结果
我们发现一种 SORL1 RNA 转录本在没有病理性 AD 的老年人群中受 SORL1-BDNF 相互作用的强烈调节，并且与弥漫性 Aβ斑块的相关性强于神经原性 Aβ斑块。相同的 SORL1-BDNF 相互作用也显著影响了 [F]Florbetapir 正电子发射断层扫描测量的 Aβ负荷。
讨论
我们的研究结果弥合了 AD 风险和韧性因素之间的差距，证明了既定的 SORL1 和 BDNF 功能基因型的相互依存作用。
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