Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer’s Disease Model

Wind-Mark, Karin; Kunze, Lea H. ; Willem, Michael; Palumbo, Giovanna ; Giudici, Camilla; Nuscher, Brigitte ; Boening, Guido ; Gildehaus, Franz J. ; Lindner, Simon ; Werner, Rudolf ; Franzmeier, Nicolai ; Gnörich, Johannes S. ; Brendel, Matthias und Zatcepin, Artem (2026): Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer’s Disease Model. In: International Journal of Molecular Sciences, Vol. 27, No. 10, 4632

Abstract

Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer’s disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. AppNL-G-F knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD.

• Item Type: Journal article
• Faculties: Medicine > Biomedical Center; Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Institute for Stroke and Dementia Research (ISD); Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Nuclear Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1422-0067
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198