21 General introduction Neuroinflammation in neurodegenerative diseases Neuroinflammation is an apparent feature of MS, however, neuroinflammation is also present in other CNS diseases (Figure 5), as well as their experimental models, albeit in different forms and gradations. For example, while ALS is primarily a neurodegenerative disease characterised by motor neuron loss, neuroinflammation plays a critical role in the degeneration of neurons in the brainstem, spinal cord and motor cortex173. Recently, it was shown that 1573 out of 2637 of genes related to inflammation were differentially expressed compared to controls in themotor cortex of people with ALS. Themost dysregulated signalling pathways are involved in antigen presentation, the complement system, and reactive oxygen species (ROS) production174. Microglia activation is correlated with disease severity in the spinal cord of ALS patients175. Additionally, one of the genes that has been implicated in the aetiology of ALS, C9orf72, is highly expressed in myeloid cells. Loss of C9orf functions results in lysosomal trafficking defects, and a reduced ability of microglia to clear cellular debris and aggregated proteins and aberrant microglia responses176. Furthermore, astrocytes are also affected in ALS showing increased expression of small heat shock protein to protect the cell against damage by refolding or promoting degradation of misfolded proteins175,177. TSPO PET studies of ALS have indicated that increased signal was caused by activated microglia while ignoring the contribution of other cell types such as astrocytes106,178-180. Over the last years, increasing insights into immunological processes in the CNS have shed light on the role of neuroinflammation in AD. The misfolded and aggregated proteins, characteristic of AD pathology in the form of Aβ plaques and neurofibrillary tangles, bind to PRRs on microglia and astrocytes, activating innate immune system cascades181. Microglia and astrocytes start engulfing Aβ fibrils, which is mostly resistant to degradation resulting in inefficient clearance of Aβ182,183. As a result, astrocytes around plaques are reactive but do not form gliotic scars. It has been suggested that astrocyte activation may even happen before microglia involvement in AD pathogenesis, where astrocyte atrophy leads to aberrant synaptic functioning resulting in cognitive deficits184. One of the most affected areas in AD is the hippocampus and several PET studies have found increased TSPO binding in the hippocampus101,185,186. However, some studies have not found differences in TSPO binding, complicating the use of TSPO PET to identify neuroinflammation in AD187-190. On the protein level, increased expression of TSPO is present in the cortex, but no studies have investigated TSPO expression in the hippocampus or have looked at the microglial states that were responsible for the increased expression191. Experimental animal models of CNS disease MS related pathology such as inflammation, neurodegeneration and demyelination is most commonly studied in EAE. EAE is a T-cell mediated disease induced by immunising mice or rats with CNS antigens. However, the clinical severity of EAE is highly dependent on the antigen, species, age, gender and strain of animals, but also the method of induction. All these factors can influence immunological processes as well as the response to therapies tested in EAE mice192 which unfortunately has resulted in a very low translation of therapeutic compounds for MS. For ALS, themost commonly used experimental model is the SOD1G93A mouse, as it was one of the first mutations discovered to be associated with ALS193. Whilst the SOD1G93A model replicates a moderate disease duration with misfolded SOD1, motor neuron loss, metabolic deficits and gliosis, most therapeutic compounds have failed to translate to humans148.
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