Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

Abstract

The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

Neuronal and Astrocyte Insulin-like Growth Factor-1 Signaling Differentially Modulates Ischemic Stroke Damage

“…We hypothesized that maintenance of astrocytic IGF-1 signaling would be essential to minimizing tissue damage. The hypothesis was built upon our published in vitro findings that the pharmacological inhibition of IGF-1R in astrocytes impairs glutamate uptake in vitro, reduces glutamate transporter availability, reduces the expression of glutamate handling machinery in vivo, and increases neurotoxicity in triple cell cultures [22]. Moreover, a recent literature review provides comprehensive insights into the essential functions that IGF-1 has in altering glutamate-induced toxicity Ge et al 2022 [36].…”

“…Whether made in the liver or by other local tissues, IGF-1 signaling is mediated by the insulin-like growth factor-1 receptor (IGF-1R) ubiquitously expression on all major cell types throughout the body, including neurons and neuroglia within the brain [19][20][21]. As described in our literature review [22], IGF-1 has the potential to act directly on neurons to provide neuroprotection following ischemic stroke or indirectly by modulating the functional responses of supporting glial cells within the damaged area. In general, neurons are the first to undergo cellular death events due to the lack of oxygen and ATP, while astrocytes readily buffer extracellular glutamate and begin to form the glial scar around the ischemic core.…”

Linking Diabetes to Alzheimer’s Disease: Potential Roles of Glucose Metabolism and Alpha-Glucosidase

“…Insulin/IGF-1 signaling pathway can mediate neuronal excitability, metabolism, and survival. Any abnormality or disruption in this pathway may trigger continuous dwindling of neurons in AD brains [ 48 , 49 ]. In addition, altered neuronal IGF-1 function can contribute to the neuronal pathology and overall synaptic caused by APP- Aβ clearance in the apolipoprotein E (APOE) ε carriers, thus possibly leading to increased neuritic plaque formation in AD [ 50 ].…”

Non-classical monocytes promote neurovascular repair in cerebral small vessel disease associated with microinfarctions via CX3CR1

“…21 Moreover, triggering receptor expressed on myeloid cells (TREM)2 regulates migration and survival of MDMs, 28 which release insulinlike growth factor (IGF)1 to promotes neurovascular protection. 29,30 Interestingly, classical monocytes can give rise to non-classical subset via activation of the transcription factor nuclear receptor subfamily 4 group A member (Nr4a)1. 13,[31][32][33] Our study aims to elucidate the role of non-classical monocytes in cSVD pathobiology and therapy.…”