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  Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau.

Brendel, M., Deussing, M., Blume, T., Kaiser, L., Probst, F., Overhoff, F., et al. (2019). Late-stage Anle138b treatment ameliorates tau pathology and metabolic decline in a mouse model of human Alzheimer's disease tau. Alzheimer's Research and Therapy, 11(1): 67. doi:10.1186/s13195-019-0522-z.

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Brendel, M., Autor
Deussing, M., Autor
Blume, T., Autor
Kaiser, L., Autor
Probst, F., Autor
Overhoff, F., Autor
Peters, F., Autor
von Ungern-Sternberg, B., Autor
Ryazanov, S.1, Autor           
Leonov, A.2, Autor           
Griesinger, C.2, Autor                 
Zwergal, A., Autor
Levin, J., Autor
Bartenstein, P., Autor
Yakushev, I., Autor
Cumming, P., Autor
Boening, G., Autor
Ziegler, S., Autor
Herms, J., Autor
Giese, A., Autor
Rominger, A., Autor mehr..
Affiliations:
1Department of NMR-based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              
2Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Schlagwörter: Anle138b; Late-stage; Neuronal injury; Small animal PET; Tau
 Zusammenfassung: Augmenting the brain clearance of toxic oligomers with small molecule modulators constitutes a promising therapeutic concept against tau deposition. However, there has been no test of this concept in animal models of Alzheimer's disease (AD) with initiation at a late disease stage. Thus, we aimed to investigate the effects of interventional late-stage Anle138b treatment, which previously indicated great potential to inhibit oligomer accumulation by binding of pathological aggregates, on the metabolic decline in transgenic mice with established tauopathy in a longitudinal 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) study.
METHODS:

Twelve transgenic mice expressing all six human tau isoforms (hTau) and ten controls were imaged by FDG-PET at baseline (14.5 months), followed by randomization into Anle138b treatment and vehicle groups for 3 months. FDG-PET was repeated after treatment for 3 months, and brains were analyzed by tau immunohistochemistry. Longitudinal changes of glucose metabolism were compared between study groups, and the end point tau load was correlated with individual FDG-PET findings.
RESULTS:

Tau pathology was significantly ameliorated by late-stage Anle138b treatment when compared to vehicle (frontal cortex - 53%, p < 0.001; hippocampus - 59%, p < 0.005). FDG-PET revealed a reversal of metabolic decline during Anle138b treatment, whereas the vehicle group showed ongoing deterioration. End point glucose metabolism in the brain of hTau mice had a strong correlation with tau deposition measured by immunohistochemistry (R = 0.92, p < 0.001).
CONCLUSION:

Late-stage oligomer modulation effectively ameliorated tau pathology in hTau mice and rescued metabolic function. Molecular imaging by FDG-PET can serve for monitoring effects of Anle138b treatment.

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Sprache(n): eng - English
 Datum: 2019-08-01
 Publikationsstatus: Online veröffentlicht
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 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1186/s13195-019-0522-z
 Art des Abschluß: -

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Titel: Alzheimer's Research and Therapy
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: 11 Band / Heft: 11 (1) Artikelnummer: 67 Start- / Endseite: - Identifikator: -