RESUMEN
BACKGROUND: Transthyretin (TTR) is a tetrameric, amyloid-ß (Aß)-binding protein, which reduces Aß toxicity. The TTR/Aß interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer's disease. OBJECTIVE: We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aß interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer's disease using positron emission tomography (PET). METHODS: Female mice (AßPPswe/PS1A246E/TTR+/-) were divided into 3 groups (nâ=â7 per group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100âmg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aß in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at ageâ=â14 months. RESULTS: Standard uptake values relative to the cerebellum (SUVr) of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from ageâ=â5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between agesâ=â5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at ageâ=â14 months. CONCLUSION: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aß deposition in certain brain regions.