アルツハイマーのバイオマーカーsTREM2が病気の原因であり、潜在的に修正可能な役割を果たす(Alzheimer’s biomarker sTREM2 plays a causal, potentially modifiable, role in disease)

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2024-05-31 ワシントン大学セントルイス校

タンパク質sTREM2はアルツハイマー病において重要な役割を果たしますが、その役割は複雑で理解が進んでいません。病気の初期段階では、健康な人と比べて脳脊髄液中のsTREM2レベルが低下し、病気が進行するにつれて異常に上昇します。この変動が病気の進行を反映するのか原因となるのかは不明です。モレキュラー・ニューロデジェネレーション誌に発表された研究で、カーロス・クルチャガ教授らは、sTREM2レベルの変動に関連する4つのゲノム領域を特定し、特定の遺伝子を突き止めました。さらに、メンデル無作為化法を用いて、sTREM2がアルツハイマー病の原因経路の一部であることを示しました。この発見は、新たに特定された遺伝子を標的にしてsTREM2レベルを調節し、病気の進行を変える可能性を開くものです。

<関連情報>

脳脊髄液中の可溶性TREM2のプロテオゲノミクスが新たな知見を提供し、アルツハイマー病の新規モジュレーターを同定する Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease

Lihua Wang,Niko-Petteri Nykänen,Daniel Western,Priyanka Gorijala,Jigyasha Timsina,Fuhai Li,Zhaohua Wang,Muhammad Ali,Chengran Yang,Menghan Liu,William Brock,Marta Marquié,Mercè Boada,Ignacio Alvarez,Miquel Aguilar,Pau Pastor,Agustín Ruiz,Raquel Puerta,Adelina Orellana,Jarod Rutledge,Hamilton Oh,Michael D Greicius,Yann Le Guen,Richard J. Perrin,… Carlos Cruchaga
Molecular Neurodegeneration  Published:03 January 2024
DOI:https://doi.org/10.1186/s13024-023-00687-4

アルツハイマーのバイオマーカーsTREM2が病気の原因であり、潜在的に修正可能な役割を果たす(Alzheimer’s biomarker sTREM2 plays a causal, potentially modifiable, role in disease)

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drive the association in MS4A locus and showed an epistatic effect for sTREM2 levels and AD risk. The novel TREM2 locus on chr 6 contains two rare missense variants (rs75932628 p.R47H, P=7.16×10-19; rs142232675 p.D87N, P=2.71×10-10) associated with sTREM2 and AD risk. The third novel locus in the TGFBR2 and RBMS3 gene region (rs73823326, P=3.86×10-9) included a regulatory variant with a microglia-specific chromatin loop for the promoter of TGFBR2. Using cell-based assays we demonstrate that overexpression and knock-down of TGFBR2, but not RBMS3, leads to significant changes of sTREM2. The last novel locus is located on the APOE region (rs11666329, P=2.52×10-8), but we demonstrated that this signal was independent of APOE genotype. This signal colocalized with cis-eQTL of NECTIN2 in the brain cortex and cis-pQTL of NECTIN2 in CSF. Overexpression of NECTIN2 led to an increase of sTREM2 supporting the genetic findings. To our knowledge, this is the largest study to date aimed at identifying genetic modifiers of CSF sTREM2. This study provided novel insights into the MS4A and TREM2 loci, two well-known AD risk genes, and identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology.

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