Browsing by Author "Wyss-Coray, Tony"

Now showing 1 - 3 of 3
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    An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease
    (Springer Nature, 2022) Jiang, Yuanbing; Zhou, Xiaopu; Wong, Hiu Yi; Ouyang, Li; Ip, Fanny C. F.; Chau, Vicky M. N.; Lau, Shun-Fat; Wu, Wei; Wong, Daniel Y. K.; Seo, Heukjin; Fu, Wing-Yu; Lai, Nicole C. H.; Chen, Yuewen; Chen, Yu; Tong, Estella P. S.; Alzheimer’s Disease Neuroimaging Initiative; Mok, Vincent C. T.; Kwok, Timothy C. Y.; Mok, Kin Y.; Shoai, Maryam; Lehallier, Benoit; Morán Losada, Patricia; O'Brien, Eleanor; Porter, Tenielle; Laws, Simon M.; Hardy, John; Wyss-Coray, Tony; Masters, Colin L.; Fu, Amy K. Y.; Ip, Nancy Y.; Radiology and Imaging Sciences, School of Medicine
    Changes in the levels of circulating proteins are associated with Alzheimer's disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33-ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR-Cas9 genome editing identified rs1921622 , a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622 , demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622 /sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD.
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    Genetic Variants of Phospholipase C-γ2 Alter the Phenotype and Function of Microglia and Confer Differential Risk for Alzheimer’s Disease
    (Elsevier, 2023) Tsai, Andy P.; Dong, Chuanpeng; Lin, Peter Bor-Chian; Oblak, Adrian L.; Di Prisco, Gonzalo Viana; Wang, Nian; Hajicek, Nicole; Carr, Adam J.; Lendy, Emma K.; Hahn, Oliver; Atkins, Micaiah; Foltz, Aulden G.; Patel, Jheel; Xu, Guixiang; Moutinho, Miguel; Sondek, John; Zhang, Qisheng; Mesecar, Andrew D.; Liu, Yunlong; Atwood, Brady K.; Wyss-Coray, Tony; Nho, Kwangsik; Bissel, Stephanie J.; Lamb, Bruce T.; Landreth, Gary E.; Medical and Molecular Genetics, School of Medicine
    Genetic association studies have demonstrated the critical involvement of the microglial immune response in Alzheimer's disease (AD) pathogenesis. Phospholipase C-gamma-2 (PLCG2) is selectively expressed by microglia and functions in many immune receptor signaling pathways. In AD, PLCG2 is induced uniquely in plaque-associated microglia. A genetic variant of PLCG2, PLCG2P522R, is a mild hypermorph that attenuates AD risk. Here, we identified a loss-of-function PLCG2 variant, PLCG2M28L, that confers an increased AD risk. PLCG2P522R attenuated disease in an amyloidogenic murine AD model, whereas PLCG2M28L exacerbated the plaque burden associated with altered phagocytosis and Aβ clearance. The variants bidirectionally modulated disease pathology by inducing distinct transcriptional programs that identified microglial subpopulations associated with protective or detrimental phenotypes. These findings identify PLCG2M28L as a potential AD risk variant and demonstrate that PLCG2 variants can differentially orchestrate microglial responses in AD pathogenesis that can be therapeutically targeted.
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    Proteomics of brain, CSF, and plasma identifies molecular signatures for distinguishing sporadic and genetic Alzheimer's disease
    (American Association for the Advancement of Science, 2023) Sung, Yun Ju; Yang, Chengran; Norton, Joanne; Johnson, Matt; Fagan, Anne; Bateman, Randall J.; Perrin, Richard J.; Morris, John C.; Farlow, Martin R.; Chhatwal, Jasmeer P.; Schofield, Peter R.; Chui, Helena; Wang, Fengxian; Novotny, Brenna; Eteleeb, Abdallah; Karch, Celeste; Schindler, Suzanne E.; Rhinn, Herve; Johnson, Erik C. B.; Oh, Hamilton Se-Hwee; Rutledge, Jarod Evert; Dammer, Eric B.; Seyfried, Nicholas T.; Wyss-Coray, Tony; Harari, Oscar; Cruchaga, Carlos; Neurology, School of Medicine
    Proteomic studies for Alzheimer's disease (AD) are instrumental in identifying AD pathways but often focus on single tissues and sporadic AD cases. Here, we present a proteomic study analyzing 1305 proteins in brain tissue, cerebrospinal fluid (CSF), and plasma from patients with sporadic AD, TREM2 risk variant carriers, patients with autosomal dominant AD (ADAD), and healthy individuals. We identified 8 brain, 40 CSF, and 9 plasma proteins that were altered in individuals with sporadic AD, and we replicated these findings in several external datasets. We identified a proteomic signature that differentiated TREM2 variant carriers from both individuals with sporadic AD and healthy individuals. The proteins associated with sporadic AD were also altered in patients with ADAD, but with a greater effect size. Brain-derived proteins associated with ADAD were also replicated in additional CSF samples. Enrichment analyses highlighted several pathways, including those implicated in AD (calcineurin and Apo E), Parkinson's disease (α-synuclein and LRRK2), and innate immune responses (SHC1, ERK-1, and SPP1). Our findings suggest that combined proteomics across brain tissue, CSF, and plasma can be used to identify markers for sporadic and genetically defined AD.