| Autor: |
Deming, Yuetiva, Filipello, Fabia, Cignarella, Francesca, Suárez‐Calvet, Marc, Morenas‐Rodríguez, Estrella, Van Hulle, Carol A., Jonaitis, Erin M., Blennow, Kaj, Zetterberg, Henrik, Asthana, Sanjay, Johnson, Sterling C., Carlsson, Cynthia M., Bendlin, Barbara B., Engelman, Corinne D., Ewers, Michael, Haass, Christian, Benitez, Bruno, Karch, Celeste M., Piccio, Laura, Cruchaga, Carlos |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2020 Supplement S11, Vol. 16 Issue 11, p1-2, 2p |
| Abstrakt: |
Background: Variants within the gene‐rich membrane‐spanning 4‐domains subfamily A (MS4A) gene region have been associated with increased or reduced risk for Alzheimer's disease (AD) by large genome‐wide association studies (GWAS). Although MS4A family members are known to be cell membrane proteins implicated in immunity, their role in AD pathogenesis has remained elusive. Another transmembrane protein with a key role in immunity is the triggering receptor expressed on myeloid cells 2 (TREM2) and low frequency variants in TREM2 have been associated with AD risk. Soluble TREM2 (sTREM2) measured in cerebrospinal fluid (CSF) has also been associated with AD. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of these immune‐related genes in AD may reveal important pathological mechanisms and identify distinct therapeutic targets. Method: We measured sTREM2 in CSF samples obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 813) and used GWAS to identify genetic modifiers of CSF sTREM2. Bioinformatics approaches and RNAseq were used to identify expression quantitative trait locus (eQTL) effects. Finally, the genetic findings were functionally validated in human macrophages by lentivirus‐mediated overexpression and antibody knockdown. Result: Common variants in the MS4A gene region were associated with CSF sTREM2, which replicated in independent datasets (n = 580). These variants included a previously reported AD risk‐reducing allele in rs1582763, which associated with increased CSF sTREM2 (β = 735, P = 1.15e‐15). This variant was found to influence gene expression of a few MS4A family members including MS4A4A in blood and brain tissue. Using cell models, we validated the genetic findings by demonstrating that changes in MS4A4A expression influenced concentration of sTREM2. Conclusion: Human genetic, molecular, and cellular findings strongly suggest that MS4A4A modulates sTREM2. As also reported by our group, CSF sTREM2 is associated with tau‐related neurodegeneration and rate of memory decline in AD. Combined, these findings provide a potential mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that sTREM2 is involved in sporadic AD pathogenesis. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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