The last scientific session for the symposium was on non-neuronal cells and comprised of speakers from around the world.
Professor Hugh Perry (Southampton, UK) gave the first presentation. He discussed the commonality between various neurodegenerative diseases and the role inflammation, microglia and macrophages play. In neurodegeneration, microglia proliferate and are primed by the molecules CSF-1 and IL-34. Microglia are considered dynamic cells and can be primed by systemic inflammation that switches the innate response to an aggressive tissue damaging phenotype, which further contributes to disease progression. ALS can be described to have common features with Alzheimer’s disease and CJD; they are progressive and fatal neurodegenerative diseases that accumulate misfolded amyloid and exhibit a predictable ‘prion-like spread’ of pathology. Moreover, there is an increase in the numbers of activated microglia, which indicates underlying neuroinflammation.
Professors Perrys lab uses a Prion disease model to elucidate the role of microglia and macrophages in chronic neurodegeneration. In wild-type animals, the normal homeostatic immune response is anti-inflammatory, however, in the diseased/injured CNS the immune system switches to a pro-inflammatory response that becomes maladaptive. Professor Perry then investigated this response in the SOD1G93A mouse model and the microglia proliferate in association with an increase in CSF-1 expression. Reducing microglia proliferation was shown to prolong the animal’s life. In Alzheimer’s disease, systemic inflammation and microglia proliferation leads to cognitive decline and this is linked with elevated TNF-alpha levels. Recent evidence has demonstrated that blocking systemic TNF-alpha leads to a better cognitive outcome. In this regard, modifying proliferation and priming of microglia offers a therapeutic target for ALS and other neurodegeneration diseases.
The second presentation, by Dr Bendotti (IRCCS, Italy), also focused on the contribution of the immune response in ALS motor neuron pathology. Like the previous talk, this presentation discussed that the initial protective inflammatory response turns maladaptive in chronic degeneration. In particular, there was a focus on the role of CC-chemokine ligand 2 (CCL2 )(also know as MCP1) and its receptor CCR2. CCL2 is a cytokine – produced by macrophages, neutrophils, epithelial and endothelial cells – that is a potent attractant for monocytes and T-Cells. CCL2 progressively increases in the CNS of ALS patients and even in pre-symptomatic mouse models. Using SOD1G93A mice, the study aimed to characterise the CCL2/CCR2 axis in CNS and PNS tissue to monitor disease progression. CCL2 mRNA was upregulated in microglia, neurons and endothelial cells at disease onset as detected using laser capture microdissection and RT-PCR. However, at the later stage of disease CCR2 was only observed in microglia and astroglia. In addition, there was an increase in CD8 T-cells in the spinal cord that was followed by a reduction in protective T-Regs. This mechanism is thought to play a role in accelerating disease progression and as such could be a potential therapeutic strategy.
Dr Ozdinler (Northwestern, USA) also discussed the role of MCP1 (CCL2) and its receptor CCR2 in disease progression. MCP1 (CCL2) is an important molecular mediator of the injury response in the CNS and is elevated in serum and CSF of ALS patients. The presentation focused on using a triple transgenic mouse, hSOD1G93A-MCP1-CCR2 to understand the cellular and molecular basis of the innate, adaptive immune response in ALS. This mouse model has the same phenotypes of ‘normal’ SOD1G93A that genetically labels MCP1 and CCR2 positive cells. Positive MCP1 cells were found in the motor cortex of pre-symptomatic mice and the CCR2 positive cells were expressing markers of monocyte infiltrates. In addition, Dr Ozdinler explained that there are different mechanisms that are responsible for corticospinal and spinal cord motor neuron susceptibility despite there being similar expression patterns of cytokines.
Dr Atassi (Mass. Gen., USA) then discussed the possibility of imaging microglia in vivo. There are numerous PET ligands that bind to translocator protein (TSPO), a protein that is highly expressed in ALS. TSPO plays a role in activated microglia, reactive astrocytes, apoptosis, the regulation of cholesterol and steroid biosynthesis and is upregulated in ALS tissue. PBR28 is one such radiotracer that binds to TSPO with high specificity and this study evaluated the spatial distribution of PRB28 in an ALS patient group. It was found that there was an increased uptake of PBR28 in the primary motor cortex, supplementary motor areas and corticospinal tracts of an ALS patient group. This increased uptake of PBR28 correlates with the pathological findings of increased active microglia in areas where motor neuron death was found in post mortem tissue. This study will help with the development of personalised medicine as well as the possibility of a diagnostic biomarker for ALS patients.
Dr Leung (University of Tasmania, Aus) gave the final talk of this session. She discussed oligodendrocyte dysfunction in ALS. In SOD1G93A mice, there are increased number of oligodendrocyte precursor proteins but a lack of new oligodendrocytes suggesting a disruption in the mechanisms of differentiation. This was investigated by using a range of antibodies that label oligodendrocytes at different stages of the differentiation process. Dr Leung explained that there was co-localisation of O4 (a marker of oligodendrocytes in the pre-myelinated stage) and GPR17 (a receptor that prevents oligodendrocyte maturation and myelin formation). This indicates that in the SOD1G93A mouse oligodendrocytes are arrested in pre-myelination stages preventing the replacement of damaged oligodendrocytes and re-myelination.
This was an absolutely fascinating session that gave the audience plenty of insight into the contributions of non-neuronal cells in ALS pathology. I would like to take this opportunity to acknowledge the Motor Neuron Disease of Victoria for their generous ‘Nina Buscombe’ Travel award that allowed myself and the other recipients from Australia the opportunity to travel to Brussels and enjoy the symposium.