Neuroinflammation in ALS: cause or consequence?

Published on June 30, 2016   39 min
0:00
Hello. I am Philip Van Damme from the University of Leuven Belgium. It is my pleasure to contribute to this lecture series about ALS, and I will talk about the role of neuroinflammation in ALS. The title of my talk is, "NeuroInflammation in ALS, Cause or Consequence?"
0:20
The signs and symptoms of amyotrophic lateral sclerosis, or ALS are caused by the degeneration of upper motor neurons in the motor cortex and lower motor neurons in the brain stem and spinal cord. This degeneration of motor neurons is the hallmark of ALS, but it can manifest itself in various ways. ALS is a heterogeneous disorder with striking variability in clinical presentation, in the genetic causes, and in the underlying disease proteins. Already at the clinical level, ALS can come in different flavors. The side of onset is mostly focal width onset in limb muscles or bulbar muscles. The age at onset has a wide range, from around 18 years of age to over 85 years. The rate of disease progression can be fast or slow. And the extent of upper versus lower motor neuron involvement, and the extent of frontal temporal involvement varies from patient to patient. Also, the genetic causes that can be identified in about 10% of patients range from missense mutations in superoxide dismutase one, or SOD1, tar DNA-binding protein for T3, or TARDBP, and fused in sarcoma, or FUS. To repeat expansions of a G-4, C-2 hexanucleotide repeat expansion in the chromozome 9 open reading frame 72, or C9orf72 gene. The underlying disease protein is mostly TDP-43, but can also be FUS, SOD1, or dipeptide repeats in the different genetic subtypes of ALS.
2:08
Common to all forms of ALS is a neuroinflammatory response. At sites of motor neuron injury, motor neuron loss and proteinaceous aggregates in surviving cells are accompanied by a glial response consisting of microgliosis and astrogliosis. In the figure, an example of microgliosis is shown by the microglial marker, Iba-1, and of astrogliosis as showed by the astroglial marker, GFAP, in ALS can be noted in the ventral horn of the spinal cord.
2:45
Although astrocytes play a very important role in the pathogenisis of ALS and can modulate to neuroinflammatory response, I will focus on the bonafide immune cells for the rest of my talk. The immune response surrounding diseased motor neurons consists of activation and proliferation of microglia, but also of infiltration of circulating T lymphocytes and macrophages from the bloodstream into the spinal cord and brain parenchyma. For the remainder of this talk, I will focus on these inflammatory cells and try to summarize our knowledge about the role of neuroinflammation in ALS. It was not possible to incorporate all literature on this topic, and I would like to apologize to the authors who are not cited here. I will first give some background information on the different cell types involved. Then, I will summarize the evidence for a neuroinflammatory response in human ALS. Finally, I will delve into the possible mechanisms of neuroinflammation in ALS.
3:54
Microglia are central to any neuroinflammatory response in the central nervous system. They are tissue resident macrophages, and highly dynamic cells, surveying their surrounding micro environment through the constant extension and retraction of their processes. They are derived from mesoderm during embryonic development, and are capable of self-renewable. Microglia are the first line immune defense against different types of injury, as they can kill pathogens, remove cell debris, trigger immune responses, and supply neurotrophic factors. Under basal conditions, they are in a quiescent state, in which they adopt a ramified or stellate morphology. Upon activation, they acquire an amoeboid morphology, and become capable of phagocytosis. Depending on the stimulus, microglia can undergo a classical activation called M1, or an alternative activation called M2. I will come back to this in a minute. But first, what factors can regulate the activation of microglia?
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Neuroinflammation in ALS: cause or consequence?

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