Exploring deregulated signals involved in motor neuron-microglia cross-talk in ALS


Part of the results discussed in this thesis was presented in the following meetings: Cunha MI, Cunha C, Vaz AR, Brites D. Studying microglial-motoneuron cross-talk in ALS pathology. 6th iMed.UL Postgraduate Students Meeting, Lisbon, July 2, 2014. [Abstract and Poster] Vaz AR. Motoneuron degeneration and glial reactivity in ALS: insights from cellular to animal models. Neuroscience Seminars at IMM 2012, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal, June 9, 2014. [Oral Communication (by invitation)]Amyotrophic Lateral Sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Neuroinflammation has shown to be a prominent pathological feature, highlighted by the presence of activated microglia, which may exert either beneficial or detrimental effects. Mutated MNs may release factors able to induce different microglial responses. However, how cells differently modulate each other remains elusive. Therefore, a better understanding of the MN-microglia signaling pathways compromised in ALS is warranted. Here, we aim (i) to uncover signaling pathways underlying MN injury and (ii) to dissect how MNs are modulating microglial response as well as the contribution of healthy microglia to rescue MN dysfunction. We focused on fractalkine-CX3XR1 axis, MFG-E8-mediated phagocytosis and HMGB1-TLR4 signaling. For this we used a MN-like cell line (NSC-34) stably transfected with human SOD1, either wild-type (wtMNs) or with G93A mutation (mMNs), alone or in mixed cultures with N9 microglial cell line. We observed a compromised viability of microglia in the presence of mMNs, yet they were more activated, as suggested by the increase of CD11b mRNA expression. The dysfunctional mechanisms associated with increased NO and decreased glutamate production by mMNs were not recovered by the presence of healthy microglia. However, the increased activity of matrix metalloproteinase -9 observed in mMNs was decreased in the presence of microglia. In addition, mMNs presented accumulation of membrane-fractalkine and, in mixed cultures, CX3CR1 mRNA expression was up-regulated in their presence. Furthermore, we showed that mMNs expressed higher levels of MFG-E8, which were further increased in the presence of microglia. Finally, both HMGB1 and TLR4 levels were also increased in mMNs, mainly in the presence of microglia. Together, these results highlight an impairment of microglial function caused by MN dysfunction and support the development of immunomodulatory strategies restoring both healthy state of microglia and MNs

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Repositório da Universidade Nova de Lisboa

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oaioai:run.unl.pt:10362/13873Last time updated on 5/11/2018View original full text link

This paper was published in Repositório da Universidade Nova de Lisboa.

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