Loss of IGF1R in Human Astrocytes Alters Complex I Activity and Support for Neurons

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.

Insulin resistance and impaired lipid metabolism as a potential link between diabetes and Alzheimer's disease

“…Depleting cholesterol in cultured neural cells impairs intracellular signaling responses to a variety of important hormones (Fukui, Ferris, & Kahn, ). This finding is in general agreement with research demonstrating that cholesterol rich lipid membrane domains are required for cultured cells to respond normally to insulin (Ratcliffe et al, ). Moreover, it was recently shown that the IR requires membrane sterol content for its kinase activity (Delle Bovi, Kim, Suresh, London, & Miller, ).…”

Loss of insulin‐like growth factor‐1 signaling in astrocytes disrupts glutamate handling

“…A few other recent studies have utilized this inhibitory approach to explore the role of IGF‐1 in regulating other aspects of astrocyte function. Antagonism of IGFR using a monoclonal antibody decreased the ability of astrocytes to protect neurons from oxidative stress (Genis et al, ; Ratcliffe et al, ).This study by Ratcliffe et al . also showed that inhibition of IGFR did not alter the neurotrophic support provided by astrocytes, as no change in neurite outgrowth was observed in neurons co‐cultured with IGFR deficient astrocytes.…”

The functional roles of IGF-1 variants in the susceptibility and clinical outcomes of mild traumatic brain injury

“…In addition, hypoxia repressed the activities of IGF-1 signaling in zebrafish embryos [44, 45]. IGF-1 signaling in human astrocytes displayed the capacity to protect neurons from oxidative stress [46]. These pathophysiological processes had also been reported as the possible link between TBI and AD [47].…”