PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
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PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. / Kleineidam, Luca; Chouraki, Vincent; Próchnicki, Tomasz; van der Lee, Sven J; Madrid-Márquez, Laura; Wagner-Thelen, Holger; Karaca, Ilker; Weinhold, Leonie; Wolfsgruber, Steffen; Boland, Anne; Martino Adami, Pamela V; Lewczuk, Piotr; Popp, Julius; Brosseron, Frederic; Jansen, Iris E; Hulsman, Marc; Kornhuber, Johannes; Peters, Oliver; Berr, Claudine; Heun, Reinhard; Frölich, Lutz; Tzourio, Christophe; Dartigues, Jean-François; Hüll, Michael; Espinosa, Ana; Hernández, Isabel; de Rojas, Itziar; Orellana, Adelina; Valero, Sergi; Stringa, Najada; van Schoor, Natasja M; Huisman, Martijn; Scheltens, Philip; Rüther, Eckart; Deleuze, Jean-Francois; Wiltfang, Jens; Tarraga, Lluis; Schmid, Matthias; Scherer, Martin; Riedel-Heller, Steffi; Heneka, Michael T; Amouyel, Philippe; Jessen, Frank; Boada, Merce; Maier, Wolfgang; Schneider, Anja; González-Pérez, Antonio; van der Flier, Wiesje M; Wagner, Michael; Lambert, Jean-Charles; Holstege, Henne; Sáez, Mª Eugenia; Latz, Eicke; Ruiz, Agustin; Ramirez, Alfredo; Alzheimer’s Disease Neuroimaging Initiative.
In: ACTA NEUROPATHOL, Vol. 139, No. 6, 06.2020, p. 1025-1044.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment
AU - Kleineidam, Luca
AU - Chouraki, Vincent
AU - Próchnicki, Tomasz
AU - van der Lee, Sven J
AU - Madrid-Márquez, Laura
AU - Wagner-Thelen, Holger
AU - Karaca, Ilker
AU - Weinhold, Leonie
AU - Wolfsgruber, Steffen
AU - Boland, Anne
AU - Martino Adami, Pamela V
AU - Lewczuk, Piotr
AU - Popp, Julius
AU - Brosseron, Frederic
AU - Jansen, Iris E
AU - Hulsman, Marc
AU - Kornhuber, Johannes
AU - Peters, Oliver
AU - Berr, Claudine
AU - Heun, Reinhard
AU - Frölich, Lutz
AU - Tzourio, Christophe
AU - Dartigues, Jean-François
AU - Hüll, Michael
AU - Espinosa, Ana
AU - Hernández, Isabel
AU - de Rojas, Itziar
AU - Orellana, Adelina
AU - Valero, Sergi
AU - Stringa, Najada
AU - van Schoor, Natasja M
AU - Huisman, Martijn
AU - Scheltens, Philip
AU - Rüther, Eckart
AU - Deleuze, Jean-Francois
AU - Wiltfang, Jens
AU - Tarraga, Lluis
AU - Schmid, Matthias
AU - Scherer, Martin
AU - Riedel-Heller, Steffi
AU - Heneka, Michael T
AU - Amouyel, Philippe
AU - Jessen, Frank
AU - Boada, Merce
AU - Maier, Wolfgang
AU - Schneider, Anja
AU - González-Pérez, Antonio
AU - van der Flier, Wiesje M
AU - Wagner, Michael
AU - Lambert, Jean-Charles
AU - Holstege, Henne
AU - Sáez, Mª Eugenia
AU - Latz, Eicke
AU - Ruiz, Agustin
AU - Ramirez, Alfredo
AU - Alzheimer’s Disease Neuroimaging Initiative
PY - 2020/6
Y1 - 2020/6
N2 - 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.
AB - 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.
U2 - 10.1007/s00401-020-02138-6
DO - 10.1007/s00401-020-02138-6
M3 - SCORING: Journal article
C2 - 32166339
VL - 139
SP - 1025
EP - 1044
JO - ACTA NEUROPATHOL
JF - ACTA NEUROPATHOL
SN - 0001-6322
IS - 6
ER -