%0 Journal Article
%A Zu, Juan
%A Li, Cong
%A Cui, Mochen
%A Liu, Xinwu
%A Pan, Zhouyang
%A Li, Xiaohe
%A Zhang, Fang
%A Gentz, Johanna
%A Mitteregger-Kretzschmar, Gerda
%A Herms, Jochen
%A Shi, Yuan
%T Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.
%J Brain
%V 149
%N 2
%@ 0006-8950
%C Oxford
%I Oxford Univ. Press
%M DZNE-2026-00166
%P 668 - 679
%D 2026
%X 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.
%K Pioglitazone: pharmacology
%K Animals
%K Alzheimer Disease: drug therapy
%K Alzheimer Disease: pathology
%K Alzheimer Disease: metabolism
%K Microglia: drug effects
%K Microglia: metabolism
%K Microglia: pathology
%K Mice
%K Synapses: drug effects
%K Synapses: pathology
%K Disease Models, Animal
%K Mice, Transgenic
%K Dendritic Spines: drug effects
%K Dendritic Spines: pathology
%K Complement C1q: metabolism
%K Mice, Inbred C57BL
%K Male
%K PPAR gamma: agonists
%K Humans
%K Alzheimer’s disease (Other)
%K microglia (Other)
%K peroxisome proliferator-activated receptor-γ (Other)
%K pioglitazone (Other)
%K synaptic plasticity (Other)
%K Pioglitazone (NLM Chemicals)
%K Complement C1q (NLM Chemicals)
%K PPAR gamma (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:41396874
%R 10.1093/brain/awaf462
%U https://pub.dzne.de/record/285042