(S)-[18F]THK5117 brain uptake is associated with Aβ plaques and MAO-B enzyme in a mouse model of Alzheimer's disease

NEUROPHARMACOLOGY

卷:196

Article

Alzghool, Obada M.^1,2,3  Rokka, Johanna¹  Lopez-Picon, Francisco R.^1,2  Snellman, Anniina^1,2  Helin, Jatta S.^1,2  Okamura, Nobuyuki⁴  Solin, Olof^1,5,6  Rinne, Juha O.^1,7  Haaparanta-Solin, Merja^1,2 

[1] Univ Turku, Turku PET Ctr, Kiinamyllynkatu 4-8, FI-20520 Turku, Finland

[2] Univ Turku, Medicity Res Lab, Tykistokatu 6 A, FI-20520 Turku, Finland

[3] Univ Turku, Drug Res Doctoral Programme, Turku, Finland

[4] Tohoku Med & Pharmaceut Univ, Fac Med, Div Pharmacol, Sendai, Miyagi, Japan

[5] Univ Turku, Dept Chem, Vatselankatu 2, FI-20500 Turku, Finland

[6] Abo Akad Univ, Turku PET Ctr, Accelerator Lab, Kiinamyllynkatu 4-8, FI-20520 Turku, Finland

[7] Turku Univ Hosp, Div Clin Neurosci, Kiinamyllynkatu 4-8, FI-20520 Turku, Finland

关键词: Alzheimer's disease;    APP;    PS1-21;    Beta-amyloid;    MAO-B;    (S)-[F-18]THK5117;    Tau;   

DOI  :  10.1016/j.neuropharm.2021.108676

来源: Elsevier

【 摘 要 】

The mouse model of beta-amyloid (A beta) deposition, APP/PS1-21, exhibits high brain uptake of the tau-tracer (S)[18F]THK5117, although no neurofibrillary tangles are present in this mouse model. For this reason we investigated (S)-[18F]THK5117 off-target binding to A beta plaques and MAO-B enzyme in APP/PS1-21 transgenic (TG) mouse model of A beta deposition. APP/PS1-21 TG and wild-type (WT) control mice in four different age groups (2-26 months) were imaged antemortem by positron emission tomography with (S)-[18F]THK5117, and then brain autoradiography. Additional animals were used for immunohistochemical staining and MAO-B enzyme blocking study with deprenyl pre-treatment. Regional standardized uptake value ratios for the cerebellum revealed a significant temporal increase in (S)-[18F]THK5117 uptake in aged TG, but not WT, brain. Immunohistochemical staining revealed a similar increase in A beta plaques but not endogenous hyper-phosphorylated tau or MAO-B enzyme, and ex vivo autography showed that uptake of (S)-[18F]THK5117 co-localized with the amyloid pathology. Deprenyl hydrochloride pre-treatment reduced the binding of (S)-[18F]THK5117 in the neocortex, hippocampus, and thalamus. This study's findings suggest that increased (S)-[18F]THK5117 binding in aging APP/PS1-21 TG mice is mainly due to increasing A beta deposition, and to a lesser extent binding to MAO-B enzyme, but not hyper-phosphorylated tau.

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