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Investigation into pathological neuronal-myeloid cell interactions and rescue of hyper-reactive immune responses in Huntington’s disease

Dobson, L; (2017) Investigation into pathological neuronal-myeloid cell interactions and rescue of hyper-reactive immune responses in Huntington’s disease. Doctoral thesis , UCL (University College London). Green open access

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DOBSON Lucianne FINAL VERSION PhD thesis. combined. 2.06.17.pdf

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Abstract

The innate immune system is known to play a significant role in the pathogenesis of Huntington’s disease (HD). However, whether the myeloid cell activation and inflammation associated with neurodegeneration and disease progression in HD is protective or damaging remains to be clearly defined. Here, neuronal-myeloid cell interactions were examined in novel co-culture models of HD, with the aim of investigating the contribution of myeloid cells to neurotoxicity or neuroprotection in the pathogenesis of HD. HD and non-HD human NSC-derived neuronal cell lines expressing human huntingtin (HTT; full-length or exon 1) were developed and characterised. These cell lines can be differentiated into mature neuronal cultures, and HD neuronal cultures expressing mutant HTT exon 1 exhibit several characteristics of pathologically affected neurons in the HD patient brain. Additionally, a novel technique was discovered for the induced differentiation of primary blood monocyte cultures, from healthy volunteers or HD patients, into microglia-like cells (BMD-microglia). BMD-microglia are similar to human brain-resident microglia in vivo by both morphological and antigenic criteria. In co-culture, BMD-microglia rescued HD neurons from mutant HTT-induced neurotoxicity and reduced neuronal death. This was associated with elevated levels of brain-derived neurotrophic factor (BDNF) release and M2 polarisation shift. During chronic stimulation, HD patient BMD-microglia became more M2-polarised than healthy volunteer BMD-microglia and released BDNF at three-fold higher levels. In contrast, BMD-macrophages, differentiated from primary monocyte cultures from healthy volunteers or HD patients, were neurotoxic in co-culture with HD or non-HD neurons, and this was associated with increased release of the proinflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)α. Inherent dysfunctional upregulation of cytokine release was also demonstrated in HD patient monocytes. Overall, the findings presented in this Thesis highlight myeloid cell phenotypes as an important modulator of neurotoxicity in HD, and harnessing the innate immune system in order to promote neuroprotective myeloid cell phenotypes whilst inhibiting neurotoxic phenotypes is an attractive therapeutic target. Laquinimod, a novel immunomodulatory drug which has been shown to have beneficial effects in multiple sclerosis patients, was shown here to dampen hyper-reactive cytokine production in HD patient monocytes. Modulation of peripheral immune responses has previously been demonstrated to impact on central pathology and disease progression in HD, and therefore laquinimod may be a promising candidate for dampening the harmful effects of a dysfunctional innate immune system in HD.

Type: Thesis (Doctoral)
Title: Investigation into pathological neuronal-myeloid cell interactions and rescue of hyper-reactive immune responses in Huntington’s disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
URI: http://discovery.ucl.ac.uk/id/eprint/1558297
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