Takalo, Mari (M);Jeskanen, Heli (H);Rolova, Taisia (T);Kervinen, Inka (I);Hellén, Marianna (M);Heikkinen, Sami (S);Koivisto, Hennariikka (H);Jokivarsi, Kimmo (K);Müller, Stephan A (SA);Koivumäki, Esa-Mikko (EM);Mäkinen, Petra (P);Juopperi, Sini-Pauliina (SP);Willman, Roosa-Maria (RM);Sinisalo, Rosa (R);Hoffmann, Dorit (D);Jäntti, Henna (H);Peitz, Michael (M);Fließbach, Klaus (K);Kuulasmaa, Teemu (T);Natunen, Teemu (T);Kemppainen, Susanna (S);Poutiainen, Pekka (P);Leinonen, Ville (V);Malm, Tarja (T);Martiskainen, Henna (H);Ramirez, Alfredo (A);Haapasalo, Annakaisa (A);Lichtenthaler, Stefan F (SF);Tanila, Heikki (H);Haass, Christian (C);Rinne, Juha (J);Koistinaho, Jari (J);Hiltunen, Mikko (M);

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J Neuroinflammation.2025 Mar 05;22(1):64.doi:10.1186/s12974-025-03387-6

Abstract

BACKGROUND: Phospholipase C gamma 2, proline 522 to arginine (PLCγ2-P522R) is a protective variant that reduces the risk of Alzheimer's disease (AD). Recently, it was shown to mitigate β-amyloid pathology in a 5XFAD mouse model of AD. Here, we investigated the protective functions of the PLCγ2-P522R variant in a less aggressive APP/PS1 mouse model of AD and assessed the underlying cellular mechanisms using mouse and human microglial models.

METHODS: The effects of the protective PLCγ2-P522R variant on microglial activation, AD-associated β-amyloid and neuronal pathologies, and behavioral changes were investigated in PLCγ2-P522R knock-in variant mice crossbred with APP/PS1 mice. Transcriptomic, proteomic, and functional studies were carried out using microglia isolated from mice carrying the PLCγ2-P522R variant. Finally, microglia-like cell models generated from human blood and skin biopsy samples of PLCγ2-P522R variant carriers were employed.

RESULTS: The PLCγ2-P522R variant decreased β-amyloid plaque count and coverage in female APP/PS1 mice. Moreover, the PLCγ2-P522R variant promoted anxiety in these mice. The area of the microglia around β-amyloid plaques was also increased in mice carrying the PLCγ2-P522R variant, while β-amyloid plaque-associated neuronal dystrophy and the levels of certain cytokines, including IL-6 and IL-1β, were reduced. These alterations were revealed through [18F]FEPPA PET imaging and behavioral studies, as well as various cytokine immunoassays, transcriptomic and proteomic analyses, and immunohistochemical analyses using mouse brain tissues. In cultured mouse primary microglia, the PLCγ2-P522R variant reduced the size of lipid droplets. Furthermore, transcriptomic and proteomic analyses revealed that the PLCγ2-P522R variant regulated key targets and pathways involved in lipid metabolism, mitochondrial fatty acid oxidation, and inflammatory/interferon signaling in acutely isolated adult mouse microglia and human monocyte-derived microglia-like cells. Finally, the PLCγ2-P522R variant also increased mitochondrial respiration in human iPSC-derived microglia.

CONCLUSIONS: These findings suggest that the PLCγ2-P522R variant exerts protective effects against β-amyloid and neuronal pathologies by increasing microglial responsiveness to β-amyloid plaques in APP/PS1 mice. The changes observed in lipid/fatty acid and mitochondrial metabolism revealed by the omics and metabolic assessments of mouse and human microglial models suggest that the protective effects of the PLCγ2-P522R variant are potentially associated with increased metabolic capacity of microglia.