Dora Brites, PhD

Professor of Physiopathology of Neuroinflammation, Professor of Histology and Embriology

Faculty of Pharmacy, Universidade de Lisboa

I. The research group

The group Neuron-Glia Biology in Health and Disease, headed by Professor Dora Brites is composed by 4 senior investigators, 2 post-doc, 4 PhD students, 5 master students and 3 research-fellows.

Major research addresses neuron-glia-vascular interactions during brain development, neurodegenerative diseases and aged-related disorders. Our recent studies highlight the microglia phenotypic heterogeneity, aberrancy of astrocytes, dysregulated inflammatory-related microRNAs and alterations in cell-to-cell trafficking as part of the underlying mechanisms of Alzheimer´s disease (AD) and Amyotrophic Lateral Sclerosis (ALS) [1-5]. Ongoing HMGB1, miR-155 and S100B targeting strategies may reveal potential benefits in ageing, AD, ALS and in demyelinating diseases [6,7]. Latest studies in ALS use markers of motor neuron degeneration [8] to modulate mSOD1 cortical astrocytes, mSOD1 microglia and their derived exosomes toward neuronal survival and exosomal restrain.

Funded ongoing research include: 1. The impact of astrocyte-derived microvesicles for motor neuron degeneration and as vehicles to delivery neuroprotective cargoes in ALS (Santa Casa da Misericórdia de Lisboa, SCML); 2. Evaluation of neurotoxic and inflammatory markers of new psychoactive substances: a European network; 3. Role of ectosomes in SNC infection by HIV and HIV-related cognitive impairment (Gilead Genese); 4. Contribution of specific astrocyte and microglia phenotypic signatures and their derived extracellular vesicles for AD-associated neurodegenerative processes and their specific phenotypes, using in vitro cultures, 3D systems and humanized chimeric mice (Project JPco-fuND-MADGIC); and 5. Characterization and modulation of miRNA profiling in glial cells derived from iPSCs generated from AD and ALS patients (SCML and JPco-fuND).

II. Participation in the MADGIC project

Prof. Dora Brites group is involved in the standardization of methods across the consortium members (WP1-Task 1.5), namely concerning the differentiation of neurons, astrocytes and microglial cells from generated iPSC lines of healthy controls and AD patients, as implemented in Koistinaho’s lab. It is leading the WP2 on the “Set-up a platform to uncover cell and non-cell autonomous mechanisms of AD, in vitro”, being responsible for the analysis, in pure and co-cultures systems, of astrocyte and microglia phenotypes, as well as cell-to-cell communication via exosomes (WP2-Tasks 2.2. and 2.3.). Further, it will be responsible for the assessment of CNS cell changes in humanized models with variable genetic background and modulation by environmental stressors (WP3-Task 3.1.), and for evaluating the efficacy of repurposing EMEA/FDA approved drugs in 3D cultures of neuronal cells generated from fAD and sAD patients, and humanized chimeric animals (WP4-Task 4.1.).

III. Key publications relevant for the project

1. Caldeira C, Oliveira AF, Cunha C, Vaz AR, Falcão AS, Fernandes A, Brites D. Microglia change from a reactive to an age-like phenotype with the time in culture. Front Cell Neurosci. 2014, 8: 152.

2. Brites D and Fernandes A. Neuroinflammation and depression: microglia activation, extracellular microvesicles and microRNA dysregulation. Front Cell Neurosci. 2015, 9: 476.

3. Janota CS, Brites D, Lemere CA, Brito MA. Glio-vascular changes during ageing in wild-type and Alzheimer’s disease-like APP/PS1 mice. Brain Res. 2015, 1620: 153-168.

4. Cunha C, Gomes C, Vaz AR and Brites D. Exploring new inflammatory biomarkers and pathways during LPS-induced M1 polarization. Mediat Inflamm 2016 (in press) doi: 10.1155/2016/6986175.

5. Cardoso FL, Herz J, Fernandes A, Rocha J, Sepodes B, Brito MA, McGavern DB, Brites D. Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects. J Neuroinflammation. 2015, 12:82.

6. Barateiro A, Afonso V, Santos G, Cerqueira JJ, Brites D, van Horssen J, Fernandes A. S100B as a biomarker and therapeutic target in multiple sclerosis. Mol Neurobiol. 2016, 53:3976-91.

7. Falcão AS, Carvalho LAR, Lidónio G, Vaz AR, Lucas SD, Moreira R, Brites D. Dipeptidyl vinyl sulfone as a novel chemical tool to inhibit HMGB1/NLRP3-inflammasome and inflamma-miRs in Aβ-mediated microglial inflammation. ACS Chem Neurosci 2017, 8: 89-99.

8. Vaz AR, Cunha C, Gomes C, Schmucki N, Barbosa M, Brites D. Glycoursodeoxycholic Acid Reduces Matrix Metalloproteinase-9 and Caspase-9 Activation in a Cellular Model of Superoxide Dismutase-1 Neurodegeneration. Mol Neurobiol. 2015, 51:864