Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer’s disease model
Year: 2025
Type: article
Abstract: Synaptic loss is an early hallmark of Alzheimer's disease (AD), predominantly driven by aberrant microglial reactivity. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist with anti-diabetic properties, has been shown to suppress microglial activity and improve cognitive performance in both AD models and clinical studies. However, whether its neuroprotective effects involve direct modulation of synaptic architecture remains unclear. Here, using longitudinal in vivo two-photon imaging, multi-channel immunohistochemistry, super-resolution confocal microscopy and three-dimensional reconstruction techniques in an AD mouse model, we analyse synaptic and microglial interactions. We show that a 4-week pioglitazone treatment preserves dendritic spine density and enhances spine stability over time. Mechanistically, pioglitazone reduces synaptic C1q deposition, thereby limiting complement-mediated microglial synaptic engulfment and attenuating synapse loss. These findings identify pioglitazone as a modulator of complement-dependent microglial synaptic pruning and support its therapeutic potential in preserving synaptic integrity during early AD pathogenesis.
Source: Brain
Authors: Juan Zu, Cong Li, Mochen Cui, Xinwu Liu, Zhouyang Pan, Xiaohe Li, Fang Zhang, Johanna Gentz, Gerda Mitteregger-Kretzschmar, Jochen Herms, Yuan Shi
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,570
Awards: Einfluss von Astrozyten auf die synaptische Funktion des AmyloidVorläuferproteins, G1789099517, G2060262474, C3: Die Rolle von TSPO in der strukturellen Plastizität dendritischer Spines unter physiologischen Bedingungen und in neurodegenerativen Erkrankungen, Die Rolle des Endozepin DiazepamBindungsinhibitor auf die strukturelle Plastizität der dendritischen Dornen bei neurodegenerativen Erkrankungen, EXC 2145: Munich Cluster for Systems Neurology (SyNergy)
OpenAlex ID: W4417416942