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

Article type: Research Article

Authors: Rejc, Luka^{a; *} | Gómez-Vallejo, Vanessa^b | Rios, Xabier^b | Cossío, Unai^b | Baz, Zuriñe^b | Mujica, Edurne^c | Gião, Tiago^{d; e} | Cotrina, Ellen Y.^f | Jiménez-Barbero, Jesús^{g; h; i} | Quintana, Jordi^{j; 2} | Arsequell, Gemma^f | Cardoso, Isabel^{d; e; *} | Llop, Jordi^{b; k; *}

Affiliations: [a] University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia | [b] CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), San Sebastián, Guipúzcoa, Spain | [c] Biochemistry and Molecular Biology, EHU-UPV, Leioa, Spain | [d] IBMC - Instituto de Biologia Molecular e Celular, Porto, Portugal | [e] i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal | [f] Institut de Química Avançada de Catalunya (I.Q.A.C.-C.S.I.C.), Barcelona, Spain | [g] CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Derio, Bizkaia, Spain | [h] Ikerbasque, Basque Foundation for Science, Bilbao, Spain | [i] Department Organic Chemistry II, Faculty Science & Technology, EHU-UPV, Leioa, Spain | [j] Plataforma Drug Discovery, Parc Científic de Barcelona (PCB), Barcelona, Spain | [k] Centro de Investigación Biomédica en Red – Enfermedades Respiratorias (CIBERES)

Correspondence: [*] Correspondence to: Luka Rejc, University of Ljubljana, Faculty of Chemistry and Chemical Technology, Večna pot 113, 1000 Ljubljana, Slovenia. Tel.: +386 1 479 8596; E-mail: [email protected], Isabel Cardoso, IBMC, Instituto de Biologia Molecular e Celular, Porto, Portugal; i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Rua Alfredo Allen 208, 4200-135 Porto, Portugal. Tel.: +351 226 074 900; E-mail: [email protected], and Jordi Llop, CIC biomaGUNE, Basque Research and Technology Alliance (BRTA), Paseo Miramón 182, 20014 San Sebastián, Guipúzcoa, Spain. Tel.: +34 943 00 53 33; E-mail: [email protected].

Note: [1] Dedicated to Gregorio Valencia. “El tiempo no es oro, el oro no vale nada. El tiempo es vida” (José Luis Sampedro).

Note: [2] Current affiliation: Research Programme on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Spain

Abstract: 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.

Keywords: Alzheimer’s disease, disease-modifying drug, positron emission tomography, small-molecule chaperones, transthyretin, TTR/Aβ interaction

DOI: 10.3233/JAD-200570

Journal: Journal of Alzheimer's Disease, vol. 77, no. 1, pp. 99-112, 2020