Barger, S. W. | bioRxiv Science

bioRxiv2026

Insulin Growth Factor 1 affects glutamate receptor activity differently in primary cultures of neocortical versus hippocampal neurons

Insulin-like growth factor-1 (IGF-1) plays a critical role in neuronal signaling. Disrupted insulin/IGF-1 signaling is implicated in Alzheimers disease, among other conditions, yet its specific influence on glutamate receptor-mediated calcium responses remains unclear. We examined the impacts of IGF-1 on glutamate receptor function in primary rat neurons monitored for intraneuronal calcium following stimulation with glutamate, AMPA, or NMDA/glycine. Pharmacological blockers (CNQX for AMPA receptors, APV for NMDA receptors, and nimodipine for L-type calcium channels) were applied to define receptor-specific contributions. In hippocampal neurons, IGF-1 and insulin altered responses to glutamate in different directions, with IGF-1 tending to evoke and enhanced response. In neocortical neurons, by contrast, IGF-1 consistently reduced glutamate- and AMPA-evoked calcium peaks, suggesting an inhibitory effect on AMPA receptors. To rule out effects on voltage-gated calcium channels downstream of AMPA receptors, we tested effects of IGF-1 on depolarization with potassium chloride; calcium elevation in this case was unaffected by IGF-1. Likewise, IGF-1 did not inhibit responses to NMDA/glycine; and IGF-1 did not affect glutamate responses in the presence of CNQX, a selective AMPA receptor blocker. These findings, combined with the observation that IGF-1 effects persisted in the presence of APV (an NMDA receptor antagonist), indicate that the inhibition of glutamate responses by IGF-1 is mediated by suppression of AMPA receptor activity. IGF-1 may thus contribute to normal neurophysiology, and given the role that glutamate receptors play in excitotoxicity, IGF-1 may confer neuroprotection in the neocortex. Disruption of IGF-1 signaling, as seen in states resembling insulin resistance, may therefore worsen glutamate-driven excitotoxicity and contribute to adverse outcomes.

neuroscience↗

bioRxiv2022

Amyloid β-peptide impacts on glucose regulation are dependent on apolipoprotein E genotype

The apolipoprotein E gene (APOE) constitutes the greatest genetic risk factor for Alzheimers disease, wherein the {varepsilon}4 allele confers a dramatically elevated risk compared to the more common {varepsilon}3 allele. Biological mechanisms that differ across these alleles have been explored in mouse models wherein the murine Apoe gene has undergone targeted replacement with sequences encoding human ApoE3 or -4 (ApoE-TR mice). Results with such models have indicated that the two variants of ApoE produce differential effects on energy metabolism, including metabolic syndrome. However, glucose regulation has not been compared in ApoE-TR mice with and without A{beta} accumulation. We crossed ApoE3- and ApoE4-TR mice with a transgenic line that accumulates human A{beta}1-42. In male ApoE3-TR mice, introduction of A{beta} caused aberrations in glucose tolerance and membrane translocation of astrocytic glucose transporter 1. Phosphorylation of Tau at AD-relevant sites was correlated with glucose intolerance. These effects appeared independent of insulin dysregulation and were not observed in females. In ApoE4-TR mice, the addition of A{beta} had no significant effects due to a trend toward perturbation of the baselines. Thus, metabolic changes may have a larger interaction with AD pathology and its consequences in individuals who do not carry an APOE {varepsilon}4 allele. The fact that ApoE4 generally failed to exacerbate the effects of A{beta} on glucose further highlights the growing distinction between the glycemic effects of A{beta} versus those of peripheral insulin resistance.

physiology↗