Browsing by Subject "Amyloid pathology"

Now showing 1 - 3 of 3
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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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    Impact of PLCG2 Alzheimer's Disease Risk and Protective Variants on Microglial Biology and Disease Pathogenesis
    (2022-09) Tsai, Andy Po-Yi; Oblak, Adrian L.; Landreth, Gary E.; Lamb, Bruce T.; Liu, Yunlong; Mckinzie, David L.; Nho, Kwangsik
    Alzheimer’s disease (AD) is typified by a robust microglial-mediated immune response. Genetic studies have demonstrated that many genes that alter AD risk are involved in the innate immune response and are primarily expressed in microglia. Among these genes is phospholipase C gamma 2 (PLCG2), a critical element for various immune receptors and a key regulatory hub for immune signaling. PLCG2 genetic variants are associated with altered AD risk. The primary objective of this thesis was to determine the role of PLCG2 in AD pathogenesis. We observed significant upregulation of PLCG2 expression in three brain regions of late-onset AD (LOAD) patients and a significant positive correlation of PLCG2 expression with amyloid plaque density. Furthermore, the differential gene expression analysis highlighted inflammatory response-related pathways. These results suggest that PLCG2 plays an important role in AD. We systematically investigated the impact of PLCG2 haploinsufficiency on the microglial response and amyloid pathology in the amyloidogenic 5xFAD mouse model. The results demonstrated that Plcg2 haploinsufficiency altered the phenotype of plaqueassociated microglia, suppressed cytokine levels, increased compact X34-positive plaque deposition, and downregulated the expression of microglial genes associated with immune cell activation and phagocytosis. Our study highlights the role of PLCG2 in immune responses; loss of function of PLCG2 exacerbates the amyloid pathology of AD. Genetic studies demonstrated that the hypermorphic P522R variant is protective and that the loss of function M28L variant confers an elevated risk for AD. Our results demonstrated that PLCG2 variants modulate disease pathologies through specific transcriptional programs. In the presence of amyloid pathology, the M28L risk variant impaired microglial response to plaques, suppressed cytokine release, downregulated disease-associated microglial genes, and increased plaque deposition. However, microglia harboring the P522R variant exhibit a transcriptional response endowing them with a protective immune response signature linked to their association with plaques and Aβ clearance, attenuating disease pathogenesis in an amyloidogenic mouse model of AD. Collectively, our study provides evidence that the M28L variant is associated with accelerated and exacerbated disease-related pathology, and conversely, the P522R variant appeared to attenuate disease severity and progression.
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    Plasma biomarkers predict amyloid pathology in cognitively normal monozygotic twins after 10 years
    (Oxford University Press, 2023-02-04) den Braber, Anouk; Verberk, Inge M. W.; Tomassen, Jori; den Dulk, Ben; Stoops, Erik; Dage, Jeffrey L.; Collij, Lyduine E.; Barkhof, Frederik; Willemsen, Gonneke; Nivard, Michel G.; van Berckel, Bart N. M.; Scheltens, Philip; Visser, Pieter Jelle; de Geus, Eco J. C.; Teunissen, Charlotte E.; Neurology, School of Medicine
    Blood-based biomarkers could prove useful to predict Alzheimer's disease core pathologies in advance of clinical symptoms. Implementation of such biomarkers requires a solid understanding of their long-term dynamics and the contribution of confounding to their association with Alzheimer's disease pathology. Here we assess the value of plasma amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein to detect early Alzheimer's disease pathology, accounting for confounding by genetic and early environmental factors. Participants were 200 monozygotic twins, aged ≥60 years with normal cognition from the european medical information framework for Alzheimer's disease study. All twins had amyloid-β status and plasma samples available at study enrolment. For 80 twins, additional plasma samples were available that had been collected approximately 10 years prior to amyloid-β status assessment. Single-molecule array assays were applied to measure amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein. Predictive value of and longitudinal change in these biomarkers were assessed using receiver operating characteristic curve analysis and linear mixed models. Amyloid pathology could be predicted using blood-based biomarkers obtained at the time of amyloid status assessment (amyloid-β1-42/1-40: area under the curve = 0.65, P = 0.01; phosphorylated-tau181: area under the curve = 0.84, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.74, P < 0.001), as well as using those obtained 10 years prior to amyloid status assessment (amyloid-β1-42/1-40: area under the curve = 0.69, P = 0.03; phosphorylated-tau181: area under the curve = 0.92, P < 0.001; glial fibrillary acidic protein: area under the curve = 0.84, P < 0.001). Longitudinally, amyloid-β1-42/1-40 levels decreased [β (SE) = -0.12 (0.01), P < 0.001] and phosphorylated-tau181 levels increased [β (SE) = 0.02 (0.01), P = 0.004]. Amyloid-β-positive individuals showed a steeper increase in phosphorylated-tau181 compared with amyloid-β-negative individuals [β (SE) = 0.06 (0.02), P = 0.004]. Also amyloid-β-positive individuals tended to show a steeper increase in glial fibrillary acidic protein [β (SE) = 0.04 (0.02), P = 0.07]. Within monozygotic twin pairs, those with higher plasma phosphorylated-tau181 and lower amyloid-β1-42/1-40 levels were more likely to be amyloid-β positive [β (SE) = 0.95 (0.26), P < 0.001; β (SE) = -0.28 (0.14), P < 0.05] indicating minimal contribution of confounding by genetic and early environmental factors. Our data support the use of amyloid-β1-42/1-40, phosphorylated-tau181 and glial fibrillary acidic protein as screening tools for Alzheimer's disease pathology in the normal aging population, which is of importance for enrolment of high-risk subjects in secondary, or even primary, prevention trials. Furthermore, these markers show potential as low-invasive monitoring tool of disease progression and possibly treatment effects in clinical trials.