Cross-disciplinary clinical-animal model-basic interactive research guide our translational approach to neurodegenerative and vascular brain disorders.
The Molecular Neurobiology group’s main focus is translational medicine targeting highly prevalent disorders: Proteopathies (TTR amyloidosis – FAP); Alzheimer's Disease) and cerebrovascular diseases. Our efforts ultimately aim at innovative biomarkers and treatment approaches.
We target transthyretin (TTR)-related diseases, using our unique pre-clinical TTR amyloidosis and TTR-KO models and well-characterized clinical cohorts from national and international collaborating centers; ongoing industry collaborations focus on new tools in the treatment of TTR diseases, like gene silencing, amyloid formation inhibition and its resolution. Alternative approaches through drug re-purposing focusing on TTR stabilizers, fibril disruptors and anti-apoptotic are also our focus. Some of these pre-clinical studies generated international phase I.II and III clinical trials and contributed to ongoing treatment (e.g. Alnylan siRNA for the treatment of FAP). In addition, our work on conditions and modulators of TTR aggregation and fibril formation using in vitro, cell culture studies and mice expressing hTTR variants hold the ultimate purpose of uncovering new biomarkers or drug targets for TTR amyloidoses.
We focus on the role of TTR in Alzheimer's Disease and in Stroke as these are the most disabling diseases in Portugal. In AD we unraveled the mechanisms by which TTR participates in Abeta peptide efflux, promoting its transport in brain-to-blood direction through the LRP1 receptor and stressed TTR angiogenic properties. Our team showed that in AD, as in FAP, TTR is an unstable tetramer, hence its reduced levels and impaired function in AD. We engaged a consortium to select compounds enhancers of the TTR-Abeta interaction, that may lead to potential modulating drugs.
In Stroke we depicted the role of TTR in brain ischemia and the molecular mechanisms by which TTR binds to the transducing receptor Megalin, acting in cell survival and dendrite preservation.
Selective recognition of human small transthyretin aggregates by a novel monoclonal antibody. Amyloid30(1):74-80, 2023. [Journal: Article] [IF: 5,5 (*)]
DOI: 10.1080/13506129.2022.2122034 SCOPUS: 85138264668
Bezerra F., Niemietz C., Schmidt H.H.J., Zibert A., Guo S., Monia B.P., Gonçalves P., Saraiva M.J., Almeida M.R.,
In vitro and in vivo effects of SerpinA1 on the modulation of transthyretin proteolysis. International Journal of Molecular Sciences22(17):, 2021. [Journal: Article] [CI: 4] [IF: 6,2]
DOI: 10.3390/ijms22179488 SCOPUS: 85114018847
Moreira J., Costelha S., Saraiva M., Saraiva M.J.,
The Expression of Chemokines Is Downregulated in a Pre-Clinical Model of TTR V30M Amyloidosis. Frontiers in Immunology12:, 2021. [Journal: Article] [CI: 3] [IF: 8,8]
DOI: 10.3389/fimmu.2021.650269 SCOPUS: 85107221502
Gião T., Saavedra J., Vieira J.R., Pinto M.T., Arsequell G., Cardoso I.,
Neuroprotection in early stages of Alzheimers disease is promoted by transthyretin angiogenic properties. Alzheimer's Research and Therapy13(1):, 2021. [Journal: Article] [CI: 5] [IF: 8,8]
DOI: 10.1186/s13195-021-00883-8 SCOPUS: 85113407514
Cotrina E.Y., Santos L.M., Rivas J., Blasi D., Leite J.P., Liz M.A., Busquets M.A., Planas A., Prohens R., Gimeno A., Jiménez-Barbero J., Gales L., Llop J., Quintana J., Cardoso I., Arsequell G.,
Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease. European Journal of Medicinal Chemistry226:, 2021. [Journal: Article] [CI: 5] [IF: 7,1]
DOI: 10.1016/j.ejmech.2021.113847 SCOPUS: 85115196147
Bezerra F., Saraiva M.J., Almeida M.R.,
Modulation of the Mechanisms Driving Transthyretin Amyloidosis. Frontiers in Molecular Neuroscience13:, 2020. [Journal: Review] [CI: 20] [IF: 5,6]
DOI: 10.3389/fnmol.2020.592644 SCOPUS: 85098104145
Gomes J.R., Lobo A., Nogueira R., Terceiro A.F., Costelha S., Lopes I.M., Magalhães A., Summavielle T., Saraiva M.J.,
Neuronal megalin mediates synaptic plasticity-a novel mechanism underlying intellectual disabilities in megalin gene pathologies. Brain Communications2(2):, 2020. [Journal: Article] [CI: 10]
DOI: 10.1093/braincomms/fcaa135 SCOPUS: 85111094479
Maia L.F., Maceski A., Conceição I., Obici L., Magalhães R., Cortese A., Leppert D., Merlini G., Kuhle J., Saraiva M.J.,
Plasma neurofilament light chain: an early biomarker for hereditary ATTR amyloid polyneuropathy. Amyloid27(2):97-102, 2020. [Journal: Article] [CI: 26] [IF: 7,1]
DOI: 10.1080/13506129.2019.1708716 SCOPUS: 85077877879
Gomes J.R., Sárkány Z., Teixeira A., Nogueira R., Cabrito I., Soares H., Wittelsberger A., Stortelers C., Macedo-Ribeiro S., Vanlandschoot P., Saraiva M.J.,
Anti-TTR Nanobodies Allow the Identification of TTR Neuritogenic Epitope Associated with TTR-Megalin Neurotrophic Activities. ACS Chemical Neuroscience10(1):704-715, 2019. [Journal: Article] [CI: 5] [IF: 4,5]
DOI: 10.1021/acschemneuro.8b00502 SCOPUS: 85055702609
Gonçalves P., Martins H., Costelha S., Saraiva M.J.,
Efficiency of siRNA for removal of transthyretin V30M in a TTR leptomeningeal animal model. Amyloid24:38-39, 2017. [Journal: Letter] [IF: 4]
DOI: 10.1080/13506129.2016.1272452 SCOPUS: 85018761744