title: Transthyretin stabilization by iododiflunisal promotes amyloid-β peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model.
abstract: Alzheimer's disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease.
authors.affiliation: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular, Porto, Portugal ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Ribeiro
authors.affiliation: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular, Porto, Portugal.
authors.forename: Sandra Marisa
authors.initials: SM
authors.lastname: Oliveira
authors.affiliation: REQUIMTE - Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Guido
authors.affiliation: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular, Porto, Portugal.
authors.forename: Ana
authors.initials: A
authors.lastname: Magalhães
authors.affiliation: Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona, Spain.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Valencia
authors.affiliation: Institut de Química Avançada de Catalunya (IQAC-CSIC), Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Arsequell
authors.affiliation: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular, Porto, Portugal ICBAS- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Saraiva
authors.affiliation: Molecular Neurobiology, IBMC- Instituto de Biologia Molecular e Celular, Porto, Portugal.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cardoso
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004061:Diflunisal / Q000031:analogs & derivatives* / Q000032:analysis / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000032:analysis / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011228:Prealbumin / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018697:Nootropic Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D011228:Prealbumin; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C504815:iododiflunisal; D004061:Diflunisal
keywords: Alzheimer's disease; amyloid-β peptide; behavior; cerebrospinal fluid; iododiflunisal; plasma; transgenic mouse; transthyretin