PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
Luca Kleineidam
(1, 2, 3)
,
Vincent Chouraki
(4, 5)
,
Tomasz Próchnicki
(1)
,
Sven J. van Der Lee
(6, 7)
,
Laura Madrid‑márquez
(8)
,
Holger Wagner-Thelen
(1, 2)
,
Ilker Karaca
(1)
,
Leonie Weinhold
(1)
,
Steffen Wolfsgruber
(1, 3)
,
Anne Boland
(9, 10)
,
Pamela V. Martino Adami
(2)
,
Piotr Lewczuk
(11, 12, 13)
,
Julius Popp
(14, 15)
,
Frederic Brosseron
(1, 3)
,
Iris E. Jansen
(6, 7)
,
Marc Hulsman
(6, 7)
,
Johannes Kornhuber
(11, 12)
,
Oliver Peters
(16, 3)
,
Claudine Berr
(17)
,
Reinhard Heun
(1)
,
Lutz Frölich
(18)
,
Christophe Tzourio
(19)
,
Jean-François Dartigues
(19)
,
Michael Hüll
(20)
,
Ana Espinosa
(21, 22)
,
Isabel Hernández
(21, 22)
,
Itziar de Rojas
(21, 22)
,
Adelina Orellana
(21)
,
Sergi Valero
(21, 22)
,
Najada Stringa
(6, 7)
,
Natasja M. van Schoor
(6, 7)
,
Martijn Huisman
(6, 7)
,
Philip Scheltens
(6, 7)
,
(adni) For The Alzheimer'S Disease Neuroimaging Initiative
,
Eckart Rüther
(23)
,
Jean-François Deleuze
(9, 10)
,
Jens Wiltfang
(23, 3, 24)
,
Lluis Tarraga
(21, 22)
,
Matthias Schmid
(3, 1)
,
Martin Scherer
(25)
,
Steffi Riedel-Heller
(26)
,
Michael T. Heneka
(1, 3, 27)
,
Philippe Amouyel
(4)
,
Frank Jessen
(3, 2)
,
Merce Boada
(21, 22)
,
Wolfgang Maier
(1, 3)
,
Anja Schneider
(1, 3)
,
Antonio González‑pérez
(8)
,
Wiesje M. van Der Flier
(6, 7)
,
Michael Wagner
(1, 3)
,
Jean-Charles Lambert
(4)
,
Henne Holstege
(6, 7)
,
Mª Eugenia Saez
(8)
,
Eicke Latz
(3, 1, 27, 28)
,
Agustin Ruiz
(21, 22)
,
Alfredo Ramirez
(1, 2)
1
University Hospital Bonn
2 Universität zu Köln = University of Cologne
3 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
4 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
5 Service d'Epidémiologie et de Santé Publique [Lille]
6 Amsterdam UMC - Amsterdam University Medical Center
7 VU - Vrije Universiteit Amsterdam [Amsterdam]
8 CAEBi - Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla]
9 CNRGH - Centre National de Recherche en Génomique Humaine
10 JACOB - Institut de Biologie François JACOB
11 Universitätsklinikum Erlangen [Erlangen]
12 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
13 University of Bialystok
14 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
15 University hospital of Zurich [Zurich]
16 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
17 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
18 Universität Heidelberg [Heidelberg] = Heidelberg University
19 BPH - Bordeaux population health
20 Albert-Ludwigs-Universität Freiburg
21 UIC - Universitat Internacional de Catalunya [Barcelona]
22 ISC - Instituto de Salud Carlos III [Madrid]
23 UMG - University Medical Center Göttingen
24 Universidade de Aveiro
25 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
26 Leipzig University / Universität Leipzig
27 UMASS - University of Massachusetts Medical School [Worcester]
28 NTNU - Norwegian University of Science and Technology [Trondheim]
2 Universität zu Köln = University of Cologne
3 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
4 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
5 Service d'Epidémiologie et de Santé Publique [Lille]
6 Amsterdam UMC - Amsterdam University Medical Center
7 VU - Vrije Universiteit Amsterdam [Amsterdam]
8 CAEBi - Centro andaluz de estudios bioinformáticos - Andalusian Bioinformatics Research Centre [Sevilla]
9 CNRGH - Centre National de Recherche en Génomique Humaine
10 JACOB - Institut de Biologie François JACOB
11 Universitätsklinikum Erlangen [Erlangen]
12 FAU - Friedrich-Alexander Universität Erlangen-Nürnberg = University of Erlangen-Nuremberg
13 University of Bialystok
14 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
15 University hospital of Zurich [Zurich]
16 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
17 PSNREC - Neuropsychiatrie : recherche épidémiologique et clinique
18 Universität Heidelberg [Heidelberg] = Heidelberg University
19 BPH - Bordeaux population health
20 Albert-Ludwigs-Universität Freiburg
21 UIC - Universitat Internacional de Catalunya [Barcelona]
22 ISC - Instituto de Salud Carlos III [Madrid]
23 UMG - University Medical Center Göttingen
24 Universidade de Aveiro
25 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
26 Leipzig University / Universität Leipzig
27 UMASS - University of Massachusetts Medical School [Worcester]
28 NTNU - Norwegian University of Science and Technology [Trondheim]
Anne Boland
- Fonction : Auteur
- PersonId : 757786
- ORCID : 0000-0001-8789-5676
Johannes Kornhuber
- Fonction : Auteur
- PersonId : 776431
- ORCID : 0000-0002-8096-3987
Christophe Tzourio
- Fonction : Auteur
- PersonId : 758563
- ORCID : 0000-0002-6517-2984
- IdRef : 069829209
Ana Espinosa
- Fonction : Auteur
- PersonId : 769914
- ORCID : 0000-0002-5626-6129
(adni) For The Alzheimer'S Disease Neuroimaging Initiative
- Fonction : Auteur
Jean-François Deleuze
- Fonction : Auteur
- PersonId : 798476
- ORCID : 0000-0002-5358-4463
Philippe Amouyel
- Fonction : Auteur
- PersonId : 756626
- ORCID : 0000-0001-9088-234X
- IdRef : 058556818
Jean-Charles Lambert
- Fonction : Auteur
- PersonId : 757776
- ORCID : 0000-0003-0829-7817
- IdRef : 12491506X
Alfredo Ramirez
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 1109405
Connectez-vous pour contacter l'auteur
Résumé
A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (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 pTau181, total tau, and Aβ1-42 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 pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 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.
Origine : Publication financée par une institution