Journal Article

DZNE-2026-00166

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pioglitazone attenuates complement-mediated microglial synaptic engulfment in an Alzheimer's disease model.

Zu, J. (First author)DZNE* ; Li, C. ; Cui, M.DZNE* ; Liu, X.DZNE* ; Pan, Z.DZNE* ; Li, X.DZNE* ; Zhang, F.DZNE* ; Gentz, J.Extern* ; Mitteregger-Kretzschmar, G. ; Herms, J.DZNE* ; Shi, Y. (Last author)DZNE*

2026
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awaf462

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.

Keyword(s): Pioglitazone: pharmacology (MeSH) ; Animals (MeSH) ; Alzheimer Disease: drug therapy (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Microglia: drug effects (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: pathology (MeSH) ; Mice (MeSH) ; Synapses: drug effects (MeSH) ; Synapses: pathology (MeSH) ; Disease Models, Animal (MeSH) ; Mice, Transgenic (MeSH) ; Dendritic Spines: drug effects (MeSH) ; Dendritic Spines: pathology (MeSH) ; Complement C1q: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Male (MeSH) ; PPAR gamma: agonists (MeSH) ; Humans (MeSH) ; Alzheimer’s disease ; microglia ; peroxisome proliferator-activated receptor-γ ; pioglitazone ; synaptic plasticity ; Pioglitazone ; Complement C1q ; PPAR gamma

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Contributing Institute(s):

1. Translational Brain Research (AG Herms)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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