IGF1 Signalling Impairment in Human Astrocytes and the Impact on Neuronal Support

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is classically characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) and research to date has largely focused on how these plaques and tangles affect neuronal function. However, there is evidence to suggest that the fundamental homeostatic support offered by astrocytes may be dysregulated early on in AD progression. Changes in cell signalling, particularly impairments in the insulin/insulin-like growth factor 1 (IGF1) pathway are now widely reported in AD and more recently, alterations to this pathway have been identified in astrocytes. The contribution of impaired insulin/IGF1 signalling in AD is unclear since there is also extensive literature showing an association between dysregulated insulin/IGF1 signalling and longevity.

The aim of this thesis is to understand how impaired IGF1 signalling affects the function of human astrocytes and their support for neurons. To achieve this, human astrocytes were treated with a monoclonal antibody (MAB391) that specifically targets insulin-like growth factor 1 receptor (IGF1R), causing downregulation of the receptor. A novel human astrocyte-neuron co-culture was developed to establish a physiologically relevant environment for the astrocytes and so that any alterations in astrocyte neuronal support could be observed. IGF1 signalling impaired astrocytes were less able to support neurons when challenged with hydrogen peroxide, as revealed in a neurite outgrowth assay. Using FACS sorting, astrocytes were enriched from the co-cultures and the transcriptomic profile of MAB391-treated astrocytes was assessed compared to control. Dysregulation in cell pathways involved in astrocyte energy metabolism were identified, with particular defects in complex I activity being validated.

Therefore, loss of IGF1R may impair astrocyte energy metabolism and reduce support for neurons in conditions of external stress. This could suggest that therapeutically restoring the IGF1 signalling pathway in astrocytes may preserve support for neurons during ageing and AD-associated stress.