Oral Treatment with Iododiflunisal Delays Hippocampal Amyloid-β Formation in a Transgenic Mouse Model of Alzheimer's Disease: A Longitudinal in vivo Molecular Imaging Study1.

Autor:	Rejc, Luka, Gómez-Vallejo, Vanessa, Rios, Xabier, Cossío, Unai, Baz, Zuriñe, Mujica, Edurne, Gião, Tiago, Cotrina, Ellen Y., Jiménez-Barbero, Jesús, Quintana, Jordi, Arsequell, Gemma, Cardoso, Isabel, Llop, Jordi
Předmět:	ALZHEIMER'S disease AMYLOID TRANSGENIC mice POSITRON emission tomography TREATMENT effectiveness SMALL molecules RESEARCH HIPPOCAMPUS (Brain) MOLECULAR diagnosis ORAL drug administration ANIMAL experimentation RESEARCH methodology SALICYLIC acid PROTEIN precursors MEDICAL cooperation EVALUATION research DIAGNOSTIC imaging COMPARATIVE studies MICE LONGITUDINAL method
Zdroj:	Journal of Alzheimer's Disease; 2020, Vol. 77 Issue 1, p99-112, 14p
Abstrakt:	Background: Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein, which reduces Aβ toxicity. The TTR/Aβ 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/Aβ 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 (AβPPswe/PS1A246E/TTR+/-) were divided into 3 groups (n = 7 per group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100 mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at age = 14 months.Results: Standard uptake values relative to the cerebellum (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. 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 age = 14 months.Conclusion: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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