title: Curcumin: A multi-target disease-modifying agent for late-stage transthyretin amyloidosis.
abstract: Transthyretin amyloidoses encompass a variety of acquired and hereditary diseases triggered by systemic extracellular accumulation of toxic transthyretin aggregates and fibrils, particularly in the peripheral nervous system. Since transthyretin amyloidoses are typically complex progressive disorders, therapeutic approaches aiming multiple molecular targets simultaneously, might improve therapy efficacy and treatment outcome. In this study, we evaluate the protective effect of physiologically achievable doses of curcumin on the cytotoxicity induced by transthyretin oligomers in vitro by showing reduction of caspase-3 activity and the levels of endoplasmic reticulum-resident chaperone binding immunoglobulin protein. When given to an aged Familial Amyloidotic Polyneuropathy mouse model, curcumin not only reduced transthyretin aggregates deposition and toxicity in both gastrointestinal tract and dorsal root ganglia but also remodeled congophilic amyloid material in tissues. In addition, curcumin enhanced internalization, intracellular transport and degradation of transthyretin oligomers by primary macrophages from aged Familial Amyloidotic Polyneuropathy transgenic mice, suggesting an impaired activation of naïve phagocytic cells exposed to transthyretin toxic intermediate species. Overall, our results clearly support curcumin or optimized derivatives as promising multi-target disease-modifying agent for late-stage transthyretin amyloidosis.
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.
authors.forename: Nelson
authors.initials: N
authors.lastname: Ferreira
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050 - 313 Porto, Portugal.
authors.forename: Nádia P
authors.initials: NP
authors.lastname: Gonçalves
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050 - 313 Porto, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Rua Alfredo Allen, 208, 4200 - 135 Porto, Portugal.|ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050 - 313 Porto, Portugal.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Almeida
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D011228:Prealbumin / Q000378:metabolism*; D051381:Rats
chemical_list: D011228:Prealbumin; C505410:Casp3 protein, rat; D053148:Caspase 3; D003474:Curcumin