PLCG2 rs72824905 Variant Reduces the Risk of Alzheimer’s Disease and Multiple Sclerosis

Fan, Chen; Zhang, Yan; Wang, Longcai; Han, Zhifa; Zhang, Haihua; Gao, Shan; Hu, Yang; Liu, Guiyou

doi:10.3233/jad-201140

Cited by 4 publications

(2 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In 2017, the protective and rare coding variant rs72824905 in PLCG2 (P522R variant) was first reported to be significantly associated with the risk of AD, and this association has been confirmed in GWAS studies in several different populations in subsequent years (Sims et al, 2017;Conway et al, 2018;Dalmasso et al, 2019;Chen et al, 2021;de Rojas et al, 2021). Recently, the P522R variant has become the most studied variant of PLCG2.…”

Section: Phospholipase C-gamma-2 Variants In Alzheimer's Diseasementioning

confidence: 90%

“…Of note, the PLCG2 P522R variant is also associated with a reduced risk for dementia subtypes other than AD, such as Lewy body and frontotemporal dementia, and is positively associated with longevity ( van der Lee et al, 2019 ; Chen et al, 2021 ). Taken together, various findings suggest that modulation of PLCγ2 signaling may be very promising for the development of AD and other neurological diseases.…”

Section: Discussion and Prospectsmentioning

confidence: 99%

See 1 more Smart Citation

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

Ran

Wang

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease mainly characterized by memory loss and cognitive decline. The etiology of AD is complex and remains incompletely understood. In recent years, genome-wide association studies (GWAS) have increasingly highlighted the central role of microglia in AD pathology. As a trans-membrane receptor specifically present on the microglia in the central nervous system, phosphatidylinositol-specific phospholipase C gamma 2 (PLCγ2) plays an important role in neuroinflammation. GWAS data and corresponding pathological research have explored the effects of PLCG2 variants on amyloid burden and tau pathologies that underline AD. The link between PLCγ2 and other AD-related effectors in human and mouse microglia has also been established, placing PLCγ2 downstream of the triggering receptor expressed on myeloid cells 2 (TREM2), toll-like receptor 4 (TLR4), Bruton’s tyrosine kinase (BTK), and colony-stimulating factor 1 receptor (CSF1R). Because the research on PLCγ2’s role in AD is still in its early stages, few articles have been published, therefore in this paper, we integrate the relevant research published to date, review the structural features, expression patterns, and related pathways of PLCγ2, and summarize the recent studies on important PLCG2 variants related to AD. Furthermore, the possibility and challenge of using PLCγ2 to develop therapeutic drugs for AD are also discussed.

show abstract

Section: Phospholipase C-gamma-2 Variants In Alzheimer's Diseasementioning

confidence: 90%

Section: Discussion and Prospectsmentioning

confidence: 99%

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

Ran

Wang

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants

Baysac,

Sun,

Nakano

et al. 2024

Journal of Allergy and Clinical Immunology

View full text Add to dashboard Cite

Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system

Diks

Teodósio

Mooij

et al. 2023

Mol Neurodegeneration

View full text Add to dashboard Cite

Background The rs72824905 single-nucleotide polymorphism in the PLCG2 gene, encoding the p.P522R residue change in Phospholipase C gamma 2 (PLCγ2), associates with protection against several dementia subtypes and with increased likelihood of longevity. Cell lines and animal models indicated that p.P522R is a functional hypermorph. We aimed to confirm this in human circulating peripheral immune cells. Methods We compared effects of p.P522R on immune system function between carriers and non-carriers (aged 59-103y), using in-depth immunophenotyping, functional B-cell and myeloid cell assays, and in vivo SARS-CoV-2 vaccination. Results In line with expectations, p.P522R impacts immune cell function only slightly, but it does so across a wide array of immune cell types. Upon B-cell stimulation, we observed increased PLCγ2 phosphorylation and calcium release, suggesting increased B-cell sensitivity upon antigen recognition. Further, p.P522R-carriers had higher numbers of CD20++CD21-CD24+ naive B cells and IgG1+ memory B cells. In myeloid cells, normalized ROS production was higher upon PLCγ2-dependent stimulation. On classical monocytes, CD33 levels were elevated. Furthermore, carriers expressed lower levels of allergy-related FcεRI on several immune cell subsets. Nevertheless, carriers and non-carriers had similar serological responses to SARS-CoV-2 vaccination. Conclusion The immune system from p.P522R-carriers is slightly more responsive to stimulation than in non-carriers.

show abstract

PLCG2 rs72824905 Variant Reduces the Risk of Alzheimer’s Disease and Multiple Sclerosis

Cited by 4 publications

References 24 publications

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants

Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system

Contact Info

Product

Resources

About