TY  - JOUR
AU  - Zu, Juan
AU  - Li, Cong
AU  - Cui, Mochen
AU  - Liu, Xinwu
AU  - Pan, Zhouyang
AU  - Li, Xiaohe
AU  - Zhang, Fang
AU  - Gentz, Johanna
AU  - Mitteregger-Kretzschmar, Gerda
AU  - Herms, Jochen
AU  - Shi, Yuan
TI  - Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.
JO  - Brain
VL  - 149
IS  - 2
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2026-00166
SP  - 668 - 679
PY  - 2026
AB  - 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.
KW  - Pioglitazone: pharmacology
KW  - Animals
KW  - Alzheimer Disease: drug therapy
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: metabolism
KW  - Microglia: drug effects
KW  - Microglia: metabolism
KW  - Microglia: pathology
KW  - Mice
KW  - Synapses: drug effects
KW  - Synapses: pathology
KW  - Disease Models, Animal
KW  - Mice, Transgenic
KW  - Dendritic Spines: drug effects
KW  - Dendritic Spines: pathology
KW  - Complement C1q: metabolism
KW  - Mice, Inbred C57BL
KW  - Male
KW  - PPAR gamma: agonists
KW  - Humans
KW  - Alzheimer’s disease (Other)
KW  - microglia (Other)
KW  - peroxisome proliferator-activated receptor-γ (Other)
KW  - pioglitazone (Other)
KW  - synaptic plasticity (Other)
KW  - Pioglitazone (NLM Chemicals)
KW  - Complement C1q (NLM Chemicals)
KW  - PPAR gamma (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41396874
DO  - DOI:10.1093/brain/awaf462
UR  - https://pub.dzne.de/record/285042
ER  -