Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation

Biechele, Gloria; Blume, Tanja; Deußing, Maximilian; Zott, Benedikt; Shi, Yuan; Xiang, Xianyuan; Franzmeier, Nicolai; Kleinberger, Gernot; Peters, Finn; Ochs, Katharina; Focke, Carola; Sacher, Christian; Wind, Karin; Schmidt, Corina; Lindner, Simon; Gildehaus, Franz-Josef; Eckenweber, Florian; Beyer, Leonie; Ungern-Sternberg, Barbara von; Bartenstein, Peter; Baumann, Karlheinz; Dorostkar, Mario M.; Rominger, Axel; Cumming, Paul; Willem, Michael; Adelsberger, Helmuth; Herms, Jochen; Brendel, Matthias

doi:10.7150/thno.64022

Cited by 15 publications

(11 citation statements)

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“…In this regard, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau [ 72 ]. Our observations also had similarities to serial preclinical studies in mouse models, where microglial activation was correlated with worse outcome parameters in the P301S tau model [ 61 ], but with improved spatial learning performance in PS2APP [ 73 , 74 ] and App NL-G-F [ 17 ] Aβ models. A clinical study in patients with AD also suggested that anterior temporal [ 11 C]PK11195 binding, a region with abundant tau but low Aβ deposition is associated with progressive cognitive decline [ 75 ].…”

Section: Discussionsupporting

confidence: 77%

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

et al. 2023

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Abstractβ-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 77%

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

et al. 2023

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“…The value of TSPO imaging in glioma was already determined in prognostication and detection of tumor heterogeneity ( 5 , 6 ). For back translation and mechanistic elucidation of observations in humans as well as for TSPO biomarker monitoring during experimental testing of therapeutics, animal models provide a tremendous value across brain diseases ( 2 , 7 , 8 ). First experimental glioblastoma investigations with murine GL261 in immunocompetent mice ( 9 ), human P3 in immunodeficient mice ( 10 ), and human U87 in immunodeficient rats ( 11 ) indicated feasibility of TSPO PET monitoring by different radiotracers.…”

Section: Introductionmentioning

confidence: 99%

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

Bartos

Kirchleitner²,

Blobner³

et al. 2022

Front. Med.

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IntroductionThe 18 kDa translocator protein (TSPO) receives growing interest as a biomarker in glioblastoma. Mouse models can serve as an important tool for the investigation of biomarkers in glioblastoma, but several glioblastoma models indicated only low TSPO-PET signals in contrast to high TSPO-PET signals of human glioblastoma. Thus, we aimed to investigate TSPO-PET imaging in the syngeneic immunocompetent SB28 mouse model, which is thought to closely represent the tumor microenvironment (TME) of human glioblastoma.MethodsDynamic TSPO-PET/CT imaging was performed for 60 min after injection of 13.6 ± 4.2 MBq [18F]GE-180. Contrast enhanced CT (ceCT) was acquired prior to PET and served for assessment of tumor volumes and attenuation correction. SB28 and sham mice were imaged at an early (week-1; n = 6 SB28, n = 6 sham) and a late time-point (week-3; n = 8 SB28, n = 9 sham) after inoculation. Standard of truth ex vivo tumor volumes were obtained for SB28 mice at the late time-point. Tracer kinetics were analyzed for the lesion site and the carotid arteries to establish an image derived input function (IDIF). TSPO-PET and ceCT lesion volumes were compared with ex vivo volumes by calculation of root-mean-square-errors (RMSE). Volumes of distribution (VTmax/mean) in the lesion were calculated using carotid IDIF and standardized uptake values (SUVmax/mean) were obtained for a 40–60 min time frame.ResultsHigher uptake rate constants (K1) were observed for week-1 SB28 tumor lesions when compared to week-3 SB28 tumor lesions. Highest agreement between TSPO-PET lesion volumes and ex vivo tumor volumes was achieved with a 50% maximum threshold (RMSE-VT: 39.7%; RMSE-SUV: 34.4%), similar to the agreement of ceCT tumor volumes (RMSE: 30.1%). Lesions of SB28 mice had higher PET signal when compared to sham mice at week-1 (VTmax 6.6 ± 2.9 vs. 3.9 ± 0.8, p = 0.035; SUVmax 2.3 ± 0.5 vs. 1.2 ± 0.1, p < 0.001) and PET signals remained at a similar level at week-3 (VTmax 5.0 ± 1.6 vs. 2.7 ± 0.8, p = 0.029; SUVmax 1.9 ± 0.5 vs. 1.2 ± 0.2, p = 0.0012). VTmax correlated with SUVmax (R2 = 0.532, p < 0.001).ConclusionTSPO-PET imaging of immunocompetent SB28 mice facilitates early detection of tumor signals over sham lesions. SB28 tumors mirror high TSPO-PET signals of human glioblastoma and could serve as a valuable translational model to study TSPO as an imaging biomarker.

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“…Hence, it reduced the number of reactive astrocytes and microglia in APP/PS1 mice, thereby showing antiinflammatory action while still promoting phagocytosis of Aβ-plaques [9]. Additionally, more recent studies have shown a positive effect of pioglitazone treatment on behavior [24] as well as a reduction in inflammation as measured by the attenuation of the TSPO-PET signal in PS2APP and APP NL-G-F mice [25].…”

Section: Discussionmentioning

confidence: 92%

Long-Term Pioglitazone Treatment Has No Significant Impact on Microglial Activation and Tau Pathology in P301S Mice

Kunze¹,

Ruch²,

Biechele³

et al. 2023

Preprint

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Neuroinflammation is one disease hallmark on the road to neurodegeneration in primary tauopathies. Thus, immunomodulation might be a suitable treatment strategy to delay or even prevent the occurrence of symptoms and thus relieve the burden for patients and caregivers. In the last years, the peroxisome proliferator-activated receptor γ (PPARγ) received increasing attention as it is immediately involved in the regulation of the immune system and can be targeted by the anti-diabetic drug pioglitazone. Previous studies have shown significant immunomodulation in amyloid-β (Aβ) mouse models by pioglitazone. In this study, we performed long-term treatment over six months in P301S mice as a tauopathy model with either pioglitazone or placebo. We performed serial 18 kDa translocator protein positron-emission-tomography (TSPO-PET) imaging and terminal immunohistochemistry to assess microglial activation during treatment. Tau pathology was quantified via immunohistochemistry at the end of the study. Long-term pioglitazone treatment had no significant effect on TSPO-PET, immunohistochemistry read-outs of microglial activation, or tau pathology levels in P301S mice. Thus, we conclude that pioglitazone modifies the time course of Aβ-dependent microglial activation, but does not significantly modulate microglial activation in response to tau pathology.

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Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation

Cited by 15 publications

References 50 publications

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

Long-Term Pioglitazone Treatment Has No Significant Impact on Microglial Activation and Tau Pathology in P301S Mice

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