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Background: Transthyretin (TTR) is a tetrameric, Amyloid-beta (Aβ)-binding protein, which has been shown to reduce Aβ toxicity both in vitro and in vivo. The ability of TTR to interact with Aβ can be enhanced by a series of small molecules that stabilize its tetrameric form. Because of this, TTR stabilizers might act as disease modifying drugs in Alzheimer Disease (AD). In this work, we monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF) and the repurposed drug tolcapone, by longitudinal assessment of Aβ deposition in an animal model of AD using positron emission tomography (PET) with [18F]florbetaben. Methods: Mice (AβPPswe/PS1A246E/TTR+/-; n=21) were divided into 3 groups (n=7 per group): iododiflunisal (IDIF)-treated, tolcapone-treated and non-treated. The treatment, administered in the drinking water at a dose of 100 mg/Kg/day, was started at 5 months of age. The level of Aβ deposition was assessed at ages=5, 9, 11, and 14 months by PET imaging using [18F]florbetaben. Treatment efficacy was determined based on radiotracer uptake in the hippocampus (HIP) and the cortex (CTX) with respect to the cerebellum (CB) and presented as standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analysis was performed at 14 months of age to further support in vivo results. Results: SUVr of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from age=5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. At age=11 months, IDIF-treated group showed significantly lower SUVr values than those obtained for non-treated animals. In tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in non-treated group. Moderate treatment effect of tolcapone suggests different mechanism of action than IDIF. No significant treatment effect was observed in CTX of IDIF- or tolcapone-treated animals. Results from IHC matched the in vivo data at age=14 months. Conclusions: The TTR stabilizer IDIF shows good Aβ-protective effect. Nevertheless, Aβ levels in treated and control animals reached similar values at the end of the study. Furthermore, differences in efficacy between IDIF and tolcapone, suggest different mechanisms of action. |
