Kleineidam, Luca, Chouraki, Vincent, Prochnicki, Tomasz, van der Lee, Sven J., Madrid-Marquez, Laura, Wagner-Thelen, Holger, Karaca, Ilker, Weinhold, Leonie, Wolfsgruber, Steffen, Boland, Anne, Adami, Pamela V. Martino, Lewczuk, Piotr, Popp, Julius ORCID: 0000-0002-0068-0312, Brosseron, Frederic, Jansen, Iris E., Hulsman, Marc, Kornhuber, Johannes, Peters, Oliver, Berr, Claudine, Heun, Reinhard, Froelich, Lutz, Tzourio, Christophe, Dartigues, Jean-Francois, Huell, Michael, Espinosa, Ana, Hernandez, Isabel, de Rojas, Itziar, Orellana, Adelina, Valero, Sergi, Stringa, Najada, van Schoor, Natasja M., Huisman, Martijn, Scheltens, Philip, Ruther, Eckart, Deleuze, Jean-Francois, Wiltfan, Jens, Tarraga, Lluis, Schmid, Matthias, Scherer, Martin, Riedel-Heller, Steffi, Heneka, Michael T., Amouyel, Philippe, Jessen, Frank, Boada, Merce, Maier, Wolfgang, Schneider, Anja, Gonzalez-Perez, Antonio, van der Flier, Wiesje M., Wagner, Michael ORCID: 0000-0003-2589-6440, Lambert, Jean-Charles, Holstege, Henne, Saez, M. Eugenia, Latz, Eicke, Ruiz, Agustin and Ramirez, Alfredo ORCID: 0000-0003-4991-763X (2020). PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta Neuropathol., 139 (6). S. 1025 - 1045. NEW YORK: SPRINGER. ISSN 1432-0533

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Abstract

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-gamma 2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau(181), total tau, and A beta(1-42) was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau(181) levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau(181) was similar to that of APOE-epsilon 4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low A beta(1-42) levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kleineidam, LucaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chouraki, VincentUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prochnicki, TomaszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Lee, Sven J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madrid-Marquez, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner-Thelen, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karaca, IlkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weinhold, LeonieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolfsgruber, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boland, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adami, Pamela V. MartinoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lewczuk, PiotrUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popp, JuliusUNSPECIFIEDorcid.org/0000-0002-0068-0312UNSPECIFIED
Brosseron, FredericUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jansen, Iris E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hulsman, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornhuber, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peters, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berr, ClaudineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heun, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Froelich, LutzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tzourio, ChristopheUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dartigues, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huell, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Espinosa, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hernandez, IsabelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Rojas, ItziarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orellana, AdelinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Valero, SergiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stringa, NajadaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Schoor, Natasja M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huisman, MartijnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheltens, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruther, EckartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiltfan, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tarraga, LluisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmid, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scherer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riedel-Heller, SteffiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heneka, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amouyel, PhilippeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jessen, FrankUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boada, MerceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gonzalez-Perez, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van der Flier, Wiesje M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagner, MichaelUNSPECIFIEDorcid.org/0000-0003-2589-6440UNSPECIFIED
Lambert, Jean-CharlesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holstege, HenneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saez, M. EugeniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Latz, EickeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ruiz, AgustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramirez, AlfredoUNSPECIFIEDorcid.org/0000-0003-4991-763XUNSPECIFIED
URN: urn:nbn:de:hbz:38-332305
DOI: 10.1007/s00401-020-02138-6
Journal or Publication Title: Acta Neuropathol.
Volume: 139
Number: 6
Page Range: S. 1025 - 1045
Date: 2020
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-0533
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SCAVENGER RECEPTOR-AI/II; RARE CODING VARIANTS; ALZHEIMERS-DISEASE; AMYLOID-BETA; FRONTOTEMPORAL DEMENTIA; COMPLEMENT RECEPTOR-3; MYELIN PHAGOCYTOSIS; SOLUBLE TREM2; SYNAPSE LOSS; RISK-FACTORSMultiple languages
Clinical Neurology; Neurosciences; PathologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33230

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