{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T20:33:33Z","timestamp":1778099613682,"version":"3.51.4"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T00:00:00Z","timestamp":1629763200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T00:00:00Z","timestamp":1629763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Norte 2020","award":["Norte-01-0145FEDER-000008- Porto Neurosciences"],"award-info":[{"award-number":["Norte-01-0145FEDER-000008- Porto Neurosciences"]}]},{"name":"Funda\u00e7\u00e3o Millennium bcp","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Alz Res Therapy"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>While still controversial, it has been demonstrated that vascular defects can precede the onset of other AD hallmarks features, making it an important therapeutic target. Given that the protein transthyretin (TTR) has been established as neuroprotective in AD, here we investigated the influence of TTR in the vasculature.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We evaluated the thickness of the basement membrane and the length of brain microvessels, by immunohistochemistry, in A\u03b2PPswe\/PS1A246E (AD) transgenic mice and non-transgenic mice (NT) bearing one (TTR+\/\u2212) or two (TTR+\/+) copies of the TTR gene. The angiogenic potential of TTR was evaluated in vitro using the tube formation assay, and in vivo using the chick chorioallantoic membrane (CAM) assay.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>AD transgenic mice with TTR genetic reduction, AD\/TTR+\/\u2212, exhibited a thicker BM in brain microvessels and decreased vessel length than animals with normal TTR levels, AD\/TTR+\/+. Further in vivo investigation, using the CAM assay, revealed that TTR is a pro-angiogenic molecule, and the neovessels formed are functional. Also, TTR increased the expression of key angiogenic molecules such as proteins interleukins 6 and 8, angiopoietin 2, and vascular endothelial growth factor, by endothelial cells, in vitro, under tube formation conditions. We showed that while TTR reduction also leads to a thicker BM in NT mice, this effect is more pronounced in AD mice than in NT animals, strengthening the idea that TTR is a neuroprotective protein. We also studied the effect of TTR tetrameric stabilization on BM thickness, showing that AD mice treated with the TTR tetrameric stabilizer iododiflunisal (IDIF) displayed a significant reduction of BM thickness and increased vessel length, when compared to non-treated littermates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our in vivo results demonstrate the involvement of TTR in angiogenesis, particularly as a modulator of vascular alterations occurring in AD. Since TTR is decreased early in AD, its tetrameric stabilization can represent a therapeutic avenue for the early treatment of AD through the maintenance of the vascular structure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13195-021-00883-8","type":"journal-article","created":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T14:07:53Z","timestamp":1629814073000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Neuroprotection in early stages of Alzheimer\u2019s disease is promoted by transthyretin angiogenic properties"],"prefix":"10.1186","volume":"13","author":[{"given":"Tiago","family":"Gi\u00e3o","sequence":"first","affiliation":[]},{"given":"Joana","family":"Saavedra","sequence":"additional","affiliation":[]},{"given":"Jos\u00e9 Ricardo","family":"Vieira","sequence":"additional","affiliation":[]},{"given":"Marta Teixeira","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Gemma","family":"Arsequell","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-7055","authenticated-orcid":false,"given":"Isabel","family":"Cardoso","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,8,24]]},"reference":[{"issue":"1","key":"883_CR1","doi-asserted-by":"publisher","first-page":"11934","DOI":"10.1038\/ncomms11934","volume":"7","author":"Y Iturria-Medina","year":"2016","unstructured":"Iturria-Medina Y, Sotero RC, Toussaint PJ, Mateos-P\u00e9rez JM, Evans AC, Weiner MW, et al. Early role of vascular dysregulation on late-onset Alzheimer\u2019s disease based on multifactorial data-driven analysis. Nat Commun. 2016;7(1):11934. https:\/\/doi.org\/10.1038\/ncomms11934.","journal-title":"Nat Commun"},{"issue":"4","key":"883_CR2","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/s00401-006-0115-3","volume":"112","author":"JE Donahue","year":"2006","unstructured":"Donahue JE, Flaherty SL, Johanson CE, Duncan JA, Silverberg GD, Miller MC, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer\u2019s disease. Acta Neuropathol. 2006;112(4):405\u201315. https:\/\/doi.org\/10.1007\/s00401-006-0115-3.","journal-title":"Acta Neuropathol"},{"issue":"7","key":"883_CR3","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1097\/00008571-200210000-00005","volume":"12","author":"S Vogelgesang","year":"2002","unstructured":"Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, Siegmund W, et al. Deposition of Alzheimer\u2019s \u03b2-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics. 2002;12(7):535\u201341. https:\/\/doi.org\/10.1097\/00008571-200210000-00005.","journal-title":"Pharmacogenetics."},{"key":"883_CR4","doi-asserted-by":"publisher","unstructured":"Daneman R, Prat A. The blood\u2013brain barrier. Cold Spring Harb Perspect Biol. 2015;7(1). https:\/\/doi.org\/10.1101\/cshperspect.a020412.","DOI":"10.1101\/cshperspect.a020412"},{"issue":"1","key":"883_CR5","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/j.1365-2990.2010.01139.x","volume":"37","author":"WR Brown","year":"2011","unstructured":"Brown WR, Thore CR. Review: Cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2011;37(1):56\u201374. https:\/\/doi.org\/10.1111\/j.1365-2990.2010.01139.x.","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"7","key":"883_CR6","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/nrn.2017.48","volume":"18","author":"K Kisler","year":"2017","unstructured":"Kisler K, Nelson AR, Montagne A, Zlokovic BV. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci. 2017;18(7):419\u201334. https:\/\/doi.org\/10.1038\/nrn.2017.48.","journal-title":"Nat Rev Neurosci"},{"issue":"8","key":"883_CR7","doi-asserted-by":"publisher","first-page":"e23789","DOI":"10.1371\/journal.pone.0023789","volume":"6","author":"KE Biron","year":"2011","unstructured":"Biron KE, Dickstein DL, Gopaul R, Jefferies WA. Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer\u2019s Disease. PLoS One. 2011;6(8):e23789. https:\/\/doi.org\/10.1371\/journal.pone.0023789.","journal-title":"PLoS One"},{"key":"883_CR8","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1080\/01616412.1993.11740127","volume":"15","author":"JC de la Torre","year":"1993","unstructured":"de la Torre JC, Mussivand T. Can disturbed brain microcirculation cause Alzheimer\u2019s disease? Neurol Res. England. 1993;15:146\u201353.","journal-title":"Neurol Res. England"},{"issue":"1","key":"883_CR9","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1023\/B:AGEN.0000037335.17717.bf","volume":"7","author":"D Paris","year":"2004","unstructured":"Paris D, Townsend K, Quadros A, Humphrey J, Sun J, Brem S, et al. Inhibition of angiogenesis by A\u03b2 peptides. Angiogenesis. 2004;7(1):75\u201385. https:\/\/doi.org\/10.1023\/B:AGEN.0000037335.17717.bf.","journal-title":"Angiogenesis."},{"issue":"1","key":"883_CR10","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.neulet.2004.05.017","volume":"366","author":"D Paris","year":"2004","unstructured":"Paris D, Patel N, DelleDonne A, Quadros A, Smeed R, Mullan M. Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci Lett. 2004;366(1):80\u20135. https:\/\/doi.org\/10.1016\/j.neulet.2004.05.017.","journal-title":"Neurosci Lett"},{"issue":"1","key":"883_CR11","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/BF00692225","volume":"49","author":"GL Mancardi","year":"1980","unstructured":"Mancardi GL, Perdelli F, Rivano C, Leonardi A, Bugiani O. Thickening of the basement membrane of cortical capillaries in Alzheimer\u2019s disease. Acta Neuropathol. 1980;49(1):79\u201383. https:\/\/doi.org\/10.1007\/BF00692225.","journal-title":"Acta Neuropathol"},{"issue":"3","key":"883_CR12","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1007\/s00401-011-0834-y","volume":"122","author":"M Merlini","year":"2011","unstructured":"Merlini M, Meyer EP, Ulmann-Schuler A, Nitsch RM. Vascular \u03b2-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcA\u03b2 mice. Acta Neuropathol. 2011;122(3):293\u2013311. https:\/\/doi.org\/10.1007\/s00401-011-0834-y.","journal-title":"Acta Neuropathol"},{"issue":"12","key":"883_CR13","doi-asserted-by":"publisher","first-page":"1936","DOI":"10.1016\/j.neurobiolaging.2008.01.017","volume":"30","author":"DR Thal","year":"2009","unstructured":"Thal DR, Capetillo-Zarate E, Larionov S, Staufenbiel M, Zurbruegg S, Beckmann N. Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiol Aging. 2009;30(12):1936\u201348. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2008.01.017.","journal-title":"Neurobiol Aging"},{"issue":"1","key":"883_CR14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/1471-2202-5-37","volume":"5","author":"O Uspenskaia","year":"2004","unstructured":"Uspenskaia O, Liebetrau M, Herms J, Danek A, Hamann GF. Aging is associated with increased collagen type IV accumulation in the basal lamina of human cerebral microvessels. BMC Neurosci. 2004;5(1):37. https:\/\/doi.org\/10.1186\/1471-2202-5-37.","journal-title":"BMC Neurosci"},{"issue":"2","key":"883_CR15","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1002\/path.1759","volume":"206","author":"J Bergstr\u00f6m","year":"2005","unstructured":"Bergstr\u00f6m J, Gustavsson A, Hellman U, Sletten K, Murphy CL, Weiss DT, et al. Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology. J Pathol England. 2005;206(2):224\u201332. https:\/\/doi.org\/10.1002\/path.1759.","journal-title":"J Pathol England"},{"issue":"18","key":"883_CR16","doi-asserted-by":"publisher","first-page":"8368","DOI":"10.1073\/pnas.91.18.8368","volume":"91","author":"AL Schwarzman","year":"1994","unstructured":"Schwarzman AL, Gregori L, Vitek MP, Lyubski S, Strittmatter WJ, Enghilde JJ, et al. Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proc Natl Acad Sci. 1994;91(18):8368\u201372. https:\/\/doi.org\/10.1073\/pnas.91.18.8368.","journal-title":"Proc Natl Acad Sci"},{"issue":"6","key":"883_CR17","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1016\/j.febslet.2008.02.034","volume":"582","author":"R Costa","year":"2008","unstructured":"Costa R, Gon\u00e7alves A, Saraiva MJ, Cardoso I. Transthyretin binding to A-Beta peptide - Impact on A-Beta fibrillogenesis and toxicity. FEBS Lett. 2008;582(6):936\u201342. https:\/\/doi.org\/10.1016\/j.febslet.2008.02.034.","journal-title":"FEBS Lett"},{"issue":"38","key":"883_CR18","doi-asserted-by":"publisher","first-page":"8276","DOI":"10.1021\/bi101280t","volume":"49","author":"J Du","year":"2010","unstructured":"Du J, Murphy RM. Characterization of the interaction of \u03b2-Amyloid with Transthyretin monomers and tetramers. Biochemistry. 2010;49(38):8276\u201389. https:\/\/doi.org\/10.1021\/bi101280t.","journal-title":"Biochemistry."},{"key":"883_CR19","doi-asserted-by":"crossref","unstructured":"Cotrina EY, Gimeno A, Llop J, Jim\u00e9nez-Barbero J, Quintana J, Valencia G, et al. Calorimetric Studies of Binary and Ternary Molecular Interactions between Transthyretin, A\u03b2 Peptides, and Small-Molecule Chaperones toward an Alternative Strategy for Alzheimer\u2019s Disease Drug Discovery. J Med Chem [Internet]. United States; 2020;63:3205\u201314. Available from: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/32124607","DOI":"10.1021\/acs.jmedchem.9b01970"},{"issue":"50","key":"883_CR20","doi-asserted-by":"publisher","first-page":"19423","DOI":"10.1523\/JNEUROSCI.2561-13.2013","volume":"33","author":"X Li","year":"2013","unstructured":"Li X, Zhang X, Ladiwala ARA, Du D, Yadav JK, Tessier PM, et al. Mechanisms of transthyretin inhibition of \u03b2-amyloid aggregation in vitro. J Neurosci. 2013;33(50):19423\u201333. https:\/\/doi.org\/10.1523\/JNEUROSCI.2561-13.2013.","journal-title":"J Neurosci"},{"issue":"17","key":"883_CR21","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.1016\/j.jmb.2018.06.005","volume":"430","author":"L Nilsson","year":"2018","unstructured":"Nilsson L, Pamr\u00e9n A, Islam T, Br\u00e4nnstr\u00f6m K, Golchin SA, Pettersson N, et al. Transthyretin Interferes with A\u03b2 Amyloid Formation by Redirecting Oligomeric Nuclei into Non-Amyloid Aggregates. J Mol Biol. 2018;430(17):2722\u201333. https:\/\/doi.org\/10.1016\/j.jmb.2018.06.005.","journal-title":"J Mol Biol"},{"issue":"3","key":"883_CR22","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1016\/0304-3940(96)12334-X","volume":"204","author":"JA Palha","year":"1996","unstructured":"Palha JA, Moreira P, Wisniewski T, Frangione B, Saraiva MJ. Transthyretin gene in Alzheimer\u2019s disease patients. Neurosci Lett. 1996;204(3):212\u20134. https:\/\/doi.org\/10.1016\/0304-3940(96)12334-X.","journal-title":"Neurosci Lett"},{"key":"883_CR23","doi-asserted-by":"crossref","unstructured":"Schwarzman AL, Goldgaber D. Interaction of transthyretin with amyloid \u03b2-protein: Binding and inhibition of amyloid formation. CIBA Found Symp. 1996:146\u201364.","DOI":"10.1002\/9780470514924.ch10"},{"key":"883_CR24","doi-asserted-by":"publisher","first-page":"2302","DOI":"10.1016\/j.bbadis.2013.09.011","volume":"1832","author":"R Cascella","year":"2013","unstructured":"Cascella R, Conti S, Mannini B, Li X, Buxbaum JN, Tiribilli B, et al. Transthyretin suppresses the toxicity of oligomers formed by misfolded proteins in vitro. Biochim Biophys Acta - Mol Basis Dis. Elsevier B.V. 2013;1832:2302\u201314.","journal-title":"Biochim Biophys Acta - Mol Basis Dis. Elsevier B.V."},{"key":"883_CR25","doi-asserted-by":"crossref","unstructured":"Alemi M, Gaiteiro C, Ribeiro CA, Santos LM, Gomes JR, Oliveira SM, et al. Transthyretin participates in beta-amyloid transport from the brain to the liver - involvement of the low-density lipoprotein receptor-related protein 1? Sci Rep Nature Publishing Group. 2016;6.","DOI":"10.1038\/srep20164"},{"issue":"8","key":"883_CR26","doi-asserted-by":"publisher","first-page":"881","DOI":"10.2174\/156720512803251057","volume":"9","author":"CA Ribeiro","year":"2012","unstructured":"Ribeiro CA, Santana I, Oliveira C, Baldeiras I, Moreira J, Saraiva MJ, et al. Transthyretin Decrease in Plasma of MCI and AD Patients: Investigation of Mechanisms for Disease Modulation. Curr Alzheimer Res. 2012;9(8):881\u20139. https:\/\/doi.org\/10.2174\/156720512803251057.","journal-title":"Curr Alzheimer Res"},{"issue":"1","key":"883_CR27","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3233\/JAD-2011-102145","volume":"25","author":"SH Han","year":"2011","unstructured":"Han SH, Jung ES, Sohn JH, Hong HJ, Hong HS, Kim JW, et al. Human serum transthyretin levels correlate inversely with Alzheimer\u2019s disease. J Alzheimers Dis. 2011;25(1):77\u201384. https:\/\/doi.org\/10.3233\/JAD-2011-102145.","journal-title":"J Alzheimers Dis"},{"issue":"2","key":"883_CR28","doi-asserted-by":"publisher","first-page":"369","DOI":"10.3233\/JAD-2011-110611","volume":"28","author":"L Velayudhan","year":"2012","unstructured":"Velayudhan L, Killick R, Hye A, Kinsey A, G\u00fcntert A, Lynham S, et al. Plasma transthyretin as a candidate marker for Alzheimer\u2019s disease. J Alzheimers Dis. 2012;28(2):369\u201375. https:\/\/doi.org\/10.3233\/JAD-2011-110611.","journal-title":"J Alzheimers Dis"},{"issue":"4","key":"883_CR29","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1136\/jnnp.63.4.506","volume":"63","author":"JM Serot","year":"1997","unstructured":"Serot JM, Christmann D, Dubost T, Couturier M. Cerebrospinal fluid transthyretin: Aging and late onset Alzheimer\u2019s disease. J Neurol Neurosurg Psychiatry. 1997;63(4):506\u20138. https:\/\/doi.org\/10.1136\/jnnp.63.4.506.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"7","key":"883_CR30","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1111\/cns.12707","volume":"23","author":"M Alemi","year":"2017","unstructured":"Alemi M, Silva SC, Santana I, Cardoso I. Transthyretin stability is critical in assisting beta amyloid clearance\u2013 Relevance of transthyretin stabilization in Alzheimer\u2019s disease. CNS Neurosci Ther. 2017;23(7):605\u201319. https:\/\/doi.org\/10.1111\/cns.12707.","journal-title":"CNS Neurosci Ther"},{"issue":"3","key":"883_CR31","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/S0014-5793(97)01398-7","volume":"418","author":"A Quintas","year":"1997","unstructured":"Quintas A, Saraiva MJ, Brito RM. The amyloidogenic potential of transthyretin variants correlates with their tendency to aggregate in solution. FEBS Lett England. 1997;418(3):297\u2013300. https:\/\/doi.org\/10.1016\/S0014-5793(97)01398-7.","journal-title":"FEBS Lett England"},{"issue":"18","key":"883_CR32","doi-asserted-by":"publisher","first-page":"2891","DOI":"10.1016\/j.febslet.2012.07.029","volume":"586","author":"MR Almeida","year":"2012","unstructured":"Almeida MR, Saraiva MJ. Clearance of extracellular misfolded proteins in systemic amyloidosis: Experience with transthyretin. FEBS Lett. 2012;586(18):2891\u20136. https:\/\/doi.org\/10.1016\/j.febslet.2012.07.029.","journal-title":"FEBS Lett"},{"issue":"5","key":"883_CR33","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1006\/jmbi.2002.5441","volume":"317","author":"I Cardoso","year":"2002","unstructured":"Cardoso I, Goldsbury CS, M\u00fcller SA, Olivieri V, Wirtz S, Damas AM, et al. Transthyretin fibrillogenesis entails the assembly of monomers: a molecular model for in vitro assembled transthyretin amyloid-like fibrils. J Mol Biol. 2002;317(5):683\u201395. https:\/\/doi.org\/10.1006\/jmbi.2002.5441.","journal-title":"J Mol Biol"},{"key":"883_CR34","doi-asserted-by":"publisher","first-page":"587","DOI":"10.2174\/156800705774322076","volume":"4","author":"MR Almeida","year":"2005","unstructured":"Almeida MR, Gales L, Damas AM, Cardoso I, Saraiva MJ. Small transthyretin (TTR) ligands as possible therapeutic agents in TTR amyloidoses. Curr Drug Targets CNS Neurol Disord. Netherlands. 2005;4:587\u201396.","journal-title":"Curr Drug Targets CNS Neurol Disord. Netherlands"},{"issue":"24","key":"883_CR35","doi-asserted-by":"publisher","first-page":"9629","DOI":"10.1073\/pnas.1121005109","volume":"109","author":"CE Bulawa","year":"2012","unstructured":"Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012;109(24):9629\u201334. https:\/\/doi.org\/10.1073\/pnas.1121005109.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"883_CR36","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1042\/BJ20040011","volume":"381","author":"MR Almeida","year":"2004","unstructured":"Almeida MR, Macedo B, Cardoso I, Alves I, Valencia G, Arsequell G, et al. Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative. Biochem J. 2004;381(2):351\u20136. https:\/\/doi.org\/10.1042\/BJ20040011.","journal-title":"Biochem J"},{"issue":"7","key":"883_CR37","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/S0968-0896(99)00066-8","volume":"7","author":"PW Baures","year":"1999","unstructured":"Baures PW, Oza VB, Peterson SA, Kelly JW. Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid. Bioorg Med Chem. 1999;7(7):1339\u201347. https:\/\/doi.org\/10.1016\/S0968-0896(99)00066-8.","journal-title":"Bioorg Med Chem"},{"issue":"26","key":"883_CR38","doi-asserted-by":"publisher","first-page":"15051","DOI":"10.1073\/pnas.93.26.15051","volume":"93","author":"GJ Miroy","year":"1996","unstructured":"Miroy GJ, Lai Z, Lashuel HA, Peterson SA, Strang C, Kelly JW. Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc Natl Acad Sci U S A. 1996;93(26):15051\u20136. https:\/\/doi.org\/10.1073\/pnas.93.26.15051.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"883_CR39","first-page":"99","volume":"77","author":"L Rejc","year":"2020","unstructured":"Rejc L, G\u00f3mez-Vallejo V, Rios X, Cossio U, Baz Z, Mujica E, et al. Oral Treatment with Iododiflunisal Delays Hippocampal Amyloid-\u03b2 Formation in a Transgenic Mouse Model of Alzheimer\u2019s Disease: A Longitudinal in vivo Molecular Imaging Study. J Alzheimer\u2019s Dis Research Square. 2020;77:99\u2013112.","journal-title":"J Alzheimer\u2019s Dis Research Square"},{"issue":"2","key":"883_CR40","doi-asserted-by":"publisher","first-page":"357","DOI":"10.3233\/JAD-131355","volume":"39","author":"CA Ribeiro","year":"2014","unstructured":"Ribeiro CA, Oliveira SM, Guido LF, Magalh\u00e3es A, Valencia G, Arsequell G, et al. Transthyretin stabilization by iododiflunisal promotes amyloid-\u03b2 peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer\u2019s disease mouse model. J Alzheimers Dis. 2014;39(2):357\u201370. https:\/\/doi.org\/10.3233\/JAD-131355.","journal-title":"J Alzheimers Dis"},{"key":"883_CR41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-37186-2","volume":"9","author":"X Rios","year":"2019","unstructured":"Rios X, G\u00f3mez-Vallejo V, Mart\u00edn A, Coss\u00edo U, Morcillo M\u00c1, Alemi M, et al. Radiochemical examination of transthyretin (TTR) brain penetration assisted by iododiflunisal, a TTR tetramer stabilizer and a new candidate drug for AD. Sci Rep. 2019;9:1\u201311.","journal-title":"Sci Rep"},{"issue":"44","key":"883_CR42","doi-asserted-by":"publisher","first-page":"31752","DOI":"10.1074\/jbc.M113.469858","volume":"288","author":"RJ Nunes","year":"2013","unstructured":"Nunes RJ, De Oliveira P, Lages A, Becker JD, Marcelino P, Barroso E, et al. Transthyretin proteins regulate angiogenesis by conferring different molecular identities to endothelial cells. J Biol Chem. 2013;288(44):31752\u201360. https:\/\/doi.org\/10.1074\/jbc.M113.469858.","journal-title":"J Biol Chem"},{"key":"883_CR43","first-page":"1188","volume":"22","author":"J Shao","year":"2016","unstructured":"Shao J, Yao Y. Transthyretin represses neovascularization in diabetic retinopathy. Mol Vis. 2016;22:1188\u201397.","journal-title":"Mol Vis"},{"issue":"2","key":"883_CR44","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1159\/000481562","volume":"43","author":"J Shao","year":"2017","unstructured":"Shao J, Yin Y, Yin X, Ji L, Xin Y, Zou J, et al. Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy. Cell Physiol Biochem. 2017;43(2):788\u2013800. https:\/\/doi.org\/10.1159\/000481562.","journal-title":"Cell Physiol Biochem"},{"issue":"3","key":"883_CR45","doi-asserted-by":"publisher","first-page":"991","DOI":"10.4049\/jimmunol.1800736","volume":"202","author":"C-C Lee","year":"2019","unstructured":"Lee C-C, Ding X, Zhao T, Wu L, Perkins S, Du H, et al. Transthyretin Stimulates Tumor Growth through Regulation of Tumor, Immune, and Endothelial Cells. J Immunol. 2019;202(3):991\u20131002. https:\/\/doi.org\/10.4049\/jimmunol.1800736.","journal-title":"J Immunol"},{"issue":"4","key":"883_CR46","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/S0896-6273(00)80974-5","volume":"19","author":"DR Borchelt","year":"1997","unstructured":"Borchelt DR, Ratovitski T, Van Lare J, Lee MK, Gonzales V, Jenkins NA, et al. Accelerated Amyloid Deposition in the Brains of Transgenic Mice Coexpressing Mutant Presenilin 1 and Amyloid Precursor Proteins. Neuron. 1997;19(4):939\u201345. https:\/\/doi.org\/10.1016\/S0896-6273(00)80974-5.","journal-title":"Neuron."},{"issue":"6","key":"883_CR47","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1073\/pnas.90.6.2375","volume":"90","author":"V Episkopou","year":"1993","unstructured":"Episkopou V, Maeda S, Nishiguchi S, Shimada K, Gaitanaris GA, Gottesman ME, et al. Disruption of the transthyretin gene results in mice with depressed levels of plasma retinol and thyroid hormone. Proc Natl Acad Sci U S A. 1993;90(6):2375\u20139. https:\/\/doi.org\/10.1073\/pnas.90.6.2375.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"883_CR48","doi-asserted-by":"publisher","first-page":"429","DOI":"10.3233\/JAD-2011-110488","volume":"27","author":"SM Oliveira","year":"2011","unstructured":"Oliveira SM, Ribeiro CA, Cardoso I, Saraiva MJ. Gender-dependent transthyretin modulation of brain amyloid-\u03b2 Levels: Evidence from a mouse model of Alzheimer\u2019s disease. J Alzheimers Dis. 2011;27(2):429\u201339. https:\/\/doi.org\/10.3233\/JAD-2011-110488.","journal-title":"J Alzheimers Dis"},{"issue":"9","key":"883_CR49","doi-asserted-by":"publisher","first-page":"2415","DOI":"10.1021\/bi00223a017","volume":"30","author":"H Furuya","year":"1991","unstructured":"Furuya H, Saraiva MJM, Alves IL, Gawinowicz MA, Saraiva MJM, Alves IL, et al. Production of Recombinant Human Transthyretin with Biological Activities toward the Understanding of the Molecular Basis of Familial Amyloidotic Polyneuropathy (FAP). Biochemistry. 1991;30(9):2415\u201321. https:\/\/doi.org\/10.1021\/bi00223a017.","journal-title":"Biochemistry."},{"issue":"3","key":"883_CR50","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/BF02820508","volume":"6","author":"MR Almeida","year":"1997","unstructured":"Almeida MR, Damas AM, Lans MC, Brouwer A, Saraiva MJ. Thyroxine binding to transthyretin Met 119: Comparative studies of different heterozygotic carriers and structural analysis. Endocrine. 1997;6(3):309\u201315. https:\/\/doi.org\/10.1007\/BF02820508.","journal-title":"Endocrine."},{"issue":"6","key":"883_CR51","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1111\/j.1471-4159.2010.07047.x","volume":"115","author":"SD Santos","year":"2010","unstructured":"Santos SD, Lambertsen KL, Clausen BH, Akinc A, Alvarez R, Finsen B, et al. CSF transthyretin neuroprotection in a mouse model of brain ischemia. J Neurochem. 2010;115(6):1434\u201344. https:\/\/doi.org\/10.1111\/j.1471-4159.2010.07047.x.","journal-title":"J Neurochem"},{"issue":"3","key":"883_CR52","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.nlm.2007.07.006","volume":"88","author":"JC Sousa","year":"2007","unstructured":"Sousa JC, Marques F, Dias-Ferreira E, Cerqueira JJ, Sousa N, Palha JA. Transthyretin influences spatial reference memory. Neurobiol Learn Mem. 2007;88(3):381\u20135. https:\/\/doi.org\/10.1016\/j.nlm.2007.07.006.","journal-title":"Neurobiol Learn Mem"},{"issue":"2","key":"883_CR53","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1111\/j.1471-4159.2007.04828.x","volume":"103","author":"CE Fleming","year":"2007","unstructured":"Fleming CE, Saraiva MJ, Sousa MM. Transthyretin enhances nerve regeneration. J Neurochem. 2007;103(2):831\u20139. https:\/\/doi.org\/10.1111\/j.1471-4159.2007.04828.x.","journal-title":"J Neurochem"},{"issue":"10","key":"883_CR54","doi-asserted-by":"publisher","first-page":"3220","DOI":"10.1523\/JNEUROSCI.6012-08.2009","volume":"29","author":"CE Fleming","year":"2009","unstructured":"Fleming CE, Mar FM, Franquinho F, Saraiva MJ, Sousa MM. Transthyretin internalization by sensory neurons is megalin mediated and necessary for its neuritogenic activity. J Neurosci. 2009;29(10):3220\u201332. https:\/\/doi.org\/10.1523\/JNEUROSCI.6012-08.2009.","journal-title":"J Neurosci"},{"key":"883_CR55","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fncel.2015.00017","volume":"9","author":"I Gonz\u00e1lez-Marrero","year":"2015","unstructured":"Gonz\u00e1lez-Marrero I, Gim\u00e9nez-Llort L, Johanson CE, Carmona-Calero EM, Casta\u00f1eyra-Ruiz L, Brito-Armas JM, et al. Choroid plexus dysfunction impairs beta-amyloid clearance in a triple transgenic mouse model of Alzheimer\u2019s disease. Front Cell Neurosci. 2015;9:1\u201310.","journal-title":"Front Cell Neurosci"},{"key":"883_CR56","first-page":"97","volume":"22","author":"M Ueno","year":"2002","unstructured":"Ueno M, Tomimoto H, Akiguchi I, Wakita H, Sakamoto H. Blood-brain barrier disruption in white matter lesions in a rat model of chronic cerebral hypoperfusion. J Cereb Blood Flow Metab. United States. 2002;22:97\u2013104.","journal-title":"United States"},{"key":"883_CR57","doi-asserted-by":"crossref","unstructured":"De Jong GI, Farkas E, Stienstra CM, Plass JRM, Keijser JN, De La Torre JC, et al. Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience [Internet] 1999;91:203\u201310. Available from: https:\/\/www.sciencedirect.com\/science\/article\/pii\/S0306452298006599, 1, DOI: 10.1016\/S0306-4522(98)00659-9","DOI":"10.1016\/S0306-4522(98)00659-9"},{"key":"883_CR58","first-page":"1607","volume":"91","author":"TM O\u2019Hearn","year":"2007","unstructured":"O\u2019Hearn TM, Fawzi A, He S, Rao NA, Lim JI. Early onset vitreous amyloidosis in familial amyloidotic polyneuropathy with a transthyretin Glu54Gly mutation is associated with elevated vitreous VEGF. Br J Ophthalmol. 2007\/05\/23. BMJ Group. 2007;91:1607\u20139.","journal-title":"BMJ Group"},{"key":"883_CR59","first-page":"759","volume":"24","author":"LJ Cehofski","year":"2018","unstructured":"Cehofski LJ, Kruse A, Alsing AN, Nielsen JE, Pedersen S, Kirkeby S, et al. Intravitreal bevacizumab upregulates transthyretin in experimental branch retinal vein occlusion. Mol Vis Molecular Vision. 2018;24:759\u201366.","journal-title":"Mol Vis Molecular Vision"},{"issue":"1","key":"883_CR60","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1242\/jcs.115.1.175","volume":"115","author":"Y Mochizuki","year":"2002","unstructured":"Mochizuki Y, Nakamura T, Kanetake H, Kanda S. Angiopoietin 2 stimulates migration and tube-like structure formation of murine brain capillary endothelial cells through c-Fes and c-Fyn. J Cell Sci. 2002;115(1):175\u201383. https:\/\/doi.org\/10.1242\/jcs.115.1.175.","journal-title":"J Cell Sci"},{"issue":"17","key":"883_CR61","doi-asserted-by":"publisher","first-page":"11205","DOI":"10.1073\/pnas.172161899","volume":"99","author":"IB Lobov","year":"2002","unstructured":"Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci U S A. 2002;99(17):11205\u201310. https:\/\/doi.org\/10.1073\/pnas.172161899.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"883_CR62","doi-asserted-by":"publisher","first-page":"e45562","DOI":"10.1371\/journal.pone.0045562","volume":"7","author":"J Dwyer","year":"2012","unstructured":"Dwyer J, Hebda JK, Le Guelte A, Galan-Moya EM, Smith SS, Azzi S, et al. Glioblastoma Cell-Secreted Interleukin-8 Induces Brain Endothelial Cell Permeability via CXCR2. PLoS One. 2012;7(9):e45562. https:\/\/doi.org\/10.1371\/journal.pone.0045562.","journal-title":"PLoS One"},{"issue":"6","key":"883_CR63","doi-asserted-by":"publisher","first-page":"3369","DOI":"10.4049\/jimmunol.170.6.3369","volume":"170","author":"A Li","year":"2003","unstructured":"Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis. J Immunol. 2003;170(6):3369\u201376. https:\/\/doi.org\/10.4049\/jimmunol.170.6.3369.","journal-title":"J Immunol"},{"issue":"6","key":"883_CR64","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1006\/cyto.1999.0599","volume":"12","author":"D Fee","year":"2000","unstructured":"Fee D, Grzybicki D, Dobbs M, Ihyer S, Clotfelter J, MacVilay S, et al. Interleukin 6 promotes vasculogenesis of murine brain microvessel endothelial cells. Cytokine. 2000;12(6):655\u201365. https:\/\/doi.org\/10.1006\/cyto.1999.0599.","journal-title":"Cytokine."},{"key":"883_CR65","doi-asserted-by":"publisher","unstructured":"Hern\u00e1ndez-Rodr\u00edguez J, Segarra M, Vilardell C, S\u00e1nchez M, Garc\u00eda-Mart\u00ednez A, Esteban MJ, et al. Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: Angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation. 2003;107(19):2428\u201334. https:\/\/doi.org\/10.1161\/01.CIR.0000066907.83923.32.","DOI":"10.1161\/01.CIR.0000066907.83923.32"},{"issue":"6","key":"883_CR66","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1161\/ATVBAHA.113.301273","volume":"33","author":"LS Hornstrup","year":"2013","unstructured":"Hornstrup LS, Frikke-Schmidt R, Nordestgaard BG, Tybjcrg-Hansen A. Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy. Arterioscler Thromb Vasc Biol. 2013;33(6):1441\u20137. https:\/\/doi.org\/10.1161\/ATVBAHA.113.301273.","journal-title":"Arterioscler Thromb Vasc Biol"}],"container-title":["Alzheimer's Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13195-021-00883-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13195-021-00883-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13195-021-00883-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T18:55:44Z","timestamp":1673117744000},"score":1,"resource":{"primary":{"URL":"https:\/\/alzres.biomedcentral.com\/articles\/10.1186\/s13195-021-00883-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,24]]},"references-count":66,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["883"],"URL":"https:\/\/doi.org\/10.1186\/s13195-021-00883-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.04.16.440131","asserted-by":"object"}]},"ISSN":["1758-9193"],"issn-type":[{"value":"1758-9193","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,24]]},"assertion":[{"value":"11 May 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All the above experiments were approved by the Institute for Research and Innovation in Health Sciences (i3s) Animal Ethics Committee and in agreement with the animal ethics regulation from Directive 2010\/63\/EU.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"143"}}