Abstract
The insulin/insulin-like growth factor 1 (IGF1) signaling pathways are implicated in longevity and in progression of Alzheimer’s disease. Previously, we showed that insulin-like growth factor 1 receptor (IGF1R) and downstream signaling transcripts are reduced in astrocytes in human brain with progression of Alzheimer’s neuropathology and developed a model of IGF1 signaling impairment in human astrocytes using an IGF1R-specific monoclonal antibody, MAB391. Here, we have established a novel human astrocyte-neuron co-culture system to determine whether loss of astrocytic IGF1R affects their support for neurons. Astrocyte-neuron co-cultures were developed using human primary astrocytes and differentiated Lund Human Mesencephalic Cells (LUHMES). Neurite outgrowth assays, performed to measure astrocytic support for neurons, showed astrocytes provided contact-mediated support for neurite outgrowth. Loss of IGF1R did not affect neurite outgrowth under control conditions but when challenged with hydrogen peroxide IGF1R-impaired astrocytes were less able to protect LUHMES. To determine how loss of IGF1R affects neuronal support MAB391-treated astrocytes were FACS sorted from GFP-LUHMES and their transcriptomic profile was investigated using microarrays. Changes in transcripts involved in astrocyte energy metabolism were identified, particularly NDUFA2 and NDUFB6, which are related to complex I assembly. Loss of complex I activity in MAB391-treated astrocytes validated these findings. In conclusion, reduced IGF1 signaling in astrocytes impairs their support for neurons under conditions of stress and this is associated with defects in the mitochondrial respiratory chain in astrocytes.
Highlights
The insulin-like growth factor 1 (IGF1) signalling pathway involves a complex network of intracellular interactions that are essential for cell survival, growth and metabolism
In order to assess whether reduced insulin-like growth factor 1 receptor (IGF1R) levels in astrocytes affected their function a human astrocyteneuron co-culture system was developed, with Lund Human Mesencephalic Cells (LUHMES) used as a neuronal readout of astrocyte support
Reduced insulin/IGF1 signaling has been demonstrated in neurons in Alzheimer’s Disease (AD) and more recently this has been shown in astrocytes (Simpson et al, 2011)
Summary
The IGF1 signalling pathway involves a complex network of intracellular interactions that are essential for cell survival, growth and metabolism. In mice, reduced IGF1 levels in the serum and cerebral cortex causes neurovascular uncoupling which is linked to loss of metabotropic receptors and impaired release of vasodilator mediators, such as arachidonic acid (Toth et al, 2015) These studies suggest that astrocytic IGF1 signaling is important for maintaining the support and protection of neurons. Lund human mesencephalic cells (LUHMES) are conditionally-immortalized neuronal precursor cells that can be differentiated over a 5-day period into postmitotic neurons (Scholz et al, 2011) They were used as a neuronal readout of astrocyte support. Fibroblasts were used as a control to ensure that effects on neurite outgrowth were specific to astrocytes
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