Journal Article

DZNE-2026-00563

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model.

Wind, K.Extern* ; Kunze, L. H.Extern* ; Willem, M. ; Palumbo, G. ; Giudici, C.DZNE* ; Nuscher, B. ; Boening, G. ; Gildehaus, F. J. ; Lindner, S. ; Werner, R. A. ; Franzmeier, N. ; Gnörich, J. S.Extern* ; Brendel, M.DZNE* ; Zatcepin, A.Extern*

2026
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms27104632

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.

Keyword(s): Animals (MeSH) ; Alzheimer Disease: drug therapy (MeSH) ; Alzheimer Disease: immunology (MeSH) ; Alzheimer Disease: diagnostic imaging (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Amyloid beta-Peptides: immunology (MeSH) ; Amyloid beta-Peptides: antagonists & inhibitors (MeSH) ; Mice (MeSH) ; Positron-Emission Tomography (MeSH) ; Disease Models, Animal (MeSH) ; Pioglitazone: pharmacology (MeSH) ; Pioglitazone: therapeutic use (MeSH) ; Neuroinflammatory Diseases: drug therapy (MeSH) ; Neuroinflammatory Diseases: diagnostic imaging (MeSH) ; Receptors, GABA: metabolism (MeSH) ; Antibodies, Monoclonal: pharmacology (MeSH) ; Antibodies, Monoclonal: therapeutic use (MeSH) ; Immunomodulation: drug effects (MeSH) ; PPAR-gamma Agonists (MeSH) ; Mice, Transgenic (MeSH) ; Microglia: metabolism (MeSH) ; Microglia: drug effects (MeSH) ; Brain (MeSH) ; Alzheimer’s disease ; TSPO-PET ; desynchronization index ; microglia ; monoclonal antibody ; neuroinflammation ; pioglitazone ; Amyloid beta-Peptides ; Pioglitazone ; Receptors, GABA ; Antibodies, Monoclonal ; PPAR-gamma Agonists ; Bzrp protein, mouse

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

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

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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