Cross-disciplinary clinical-animal model-basic interactive research guide our translational approach on neurodegenerative and vascular brain disorders.
The Molecular Neurobiology group’s main focus is translational medicine targeting highly prevalent disorders: Proteopathies (TTR amyloidosis; 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 models for TTR amyloidosis 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 fibril disruptors and anti-inflammatories are also underway. Some of these pre-clinical studies generated international phase III clinical trials (Doxy-TUDCA for TTR Amyloidoses, from Pavia University, Italy) and contributed to ongoing treatment (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. 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.
To bring our findings closer to the clinic on cerebrovascular diseases, parallel animal models and clinical cohorts studies on acute stroke and vascular cognitive impairment are being used for the discovery of new biomarkers (genomic and proteomic) for diagnosis and management of these brain disorders. Ultimately, a multi-marker panel will be designed for more accurate diagnosis allowing better patient stratification for treatment.
In vitro and in vivo effects of SerpinA1 on the modulation of transthyretin proteolysis. International Journal of Molecular Sciences22(17):, 2021. [Journal: Article] [CI: 3] [IF: 5,9 (*)]
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] [IF: 7,6 (*)]
DOI: 10.3389/fimmu.2021.650269 SCOPUS: 85107221502
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: 9] [IF: 7,1]
DOI: 10.1080/13506129.2019.1708716 SCOPUS: 85077877879
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
Gonçalves N.P., Gonçalves P., Magalhães J., Ventosa M., Coelho A.V., Saraiva M.J.,
Tissue remodeling after interference RNA mediated knockdown of transthyretin in a familial amyloidotic polyneuropathy mouse model. Neurobiology of Aging47:91-101, 2016. [Journal: Article] [CI: 5] [IF: 5,1]
DOI: 10.1016/j.neurobiolaging.2016.07.020 SCOPUS: 84983775600
Alemi M., Gaiteiro C., Ribeiro C.A., Santos L.M., Gomes J.R., Oliveira S.M., Couraud P.O., Weksler B., Romero I., Saraiva M.J., Cardoso I.,
Transthyretin participates in beta-amyloid transport from the brain to the liver- involvement of the low-density lipoprotein receptor-related protein 1?. Scientific Reports6:, 2016. [Journal: Article] [CI: 46] [IF: 4,3]
DOI: 10.1038/srep20164 SCOPUS: 84957818760
Ribeiro C.A., Oliveira S.M., Guido L.F., Magalhães A., Valencia G., Arsequell G., Saraiva M.J., Cardoso I.,
Transthyretin stabilization by iododiflunisal promotes amyloid-ß peptide clearance, decreases its deposition, and ameliorates cognitive deficits in an Alzheimer's disease mouse model. Journal of Alzheimer's Disease39(2):357-370, 2014. [Journal: Article] [CI: 35] [IF: 4,2]
DOI: 10.3233/JAD-131355 SCOPUS: 84893904524
Gonçalves N.P., Vieira P., Saraiva M.J.,
Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis. Amyloid21(3):175-184, 2014. [Journal: Article] [CI: 31] [IF: 2]
DOI: 10.3109/13506129.2014.927759 SCOPUS: 84906229959
Gonçalves N.P., Teixeira-Coelho M., Saraiva M.J.,
The inflammatory response to sciatic nerve injury in a familial amyloidotic polyneuropathy mouse model. Experimental Neurology257:76-87, 2014. [Journal: Article] [CI: 19] [IF: 4,7]
DOI: 10.1016/j.expneurol.2014.04.030 SCOPUS: 84900864199