Attenuation of Ca2+ signaling by overexpression of PMCA2 affects the microglial response to pathological events

Microglia strongly impact the pathologic course of brain diseases and injuries. Intracellular Ca²⁺ dynamics serve as central integrators, connecting microglial sensing capacity to their responses. We generated a mouse line with microglial overexpression of plasma membrane Ca²⁺-ATPase (PMCA)2, a central regulator of cytoplasmic Ca²⁺ homeostasis. This manipulation significantly attenuated ATP-evoked Ca²⁺ signals in vitro and spontaneous Ca²⁺ transients in vivo. Notably, in contrast to astrocytes, PMCA2 overexpression in microglia/macrophages did not affect animal behavior and survival. It had, however, a profound impact on microglial reactivity in pathological contexts, including reduced inflammatory responses following lipopolysaccharide challenge and diminished microglial proliferation at sites of acute injury. In an Alzheimer’s disease model, PMCA2 overexpression attenuated the disease-associated microglial signature, reducing amyloid plaque burden and plaque-associated neuritic dystrophy. These findings highlight the importance of Ca²⁺-mediated signaling for modulating the microglial response to pathologic events. Attenuating microglial Ca²⁺ signaling by PMCA2 overexpression is a potential strategy to promote beneficial microglial phenotypes in brain inflammation or degeneration.