A Putative Mechanism of Age-Related Synaptic Dysfunction Based on the Impact of IGF-1 Receptor Signaling on Synaptic CaMKIIα Phosphorylation

Abstract

Insulin-like growth factor 1 receptor (IGF-1R) signaling regulates the activity and phosphorylation of downstream kinases linked to inflammation, neurodevelopment, aging and synaptic function. In addition to the control of Ca2+ currents, IGF-1R signaling modulates the activity of calcium-calmodulin-dependent kinase 2 alpha (CaMKIIα) and mitogen activated protein kinase (MAPK/ErK) through multiple signaling pathways. These proteins (CaMKIIα and MAPK) regulate Ca2+ movement and long-term potentiation (LTP). Since IGF-1R controls the synaptic activity of Ca2+, CaMKIIα and MAPK signaling, the possible mechanism through which an age-dependent change in IGF-1R can alter the synaptic expression and phosphorylation of these proteins in aging needs to be investigated. In this study, we evaluated the relationship between an age-dependent change in brain IGF-1R and phosphorylation of CaMKIIα/MAPK. Furthermore, we elucidated possible mechanisms through which dysregulated CaMKIIα/MAPK interaction may be linked to a change in neurotransmitter processing and synaptic function. Male C57BL/6 VGAT-Venus mice at postnatal days 80 (P80), 365 and 730 were used to study age-related neural changes in two brain regions associated with cognitive function: hippocampus and prefrontal cortex (PFC). By means of high throughput confocal imaging and quantitative immunoblotting, we evaluated the distribution and expression of IGF-1, IGF-1R, CaMKIIα, p-CaMKIIα, MAPK and p-MAPK in whole brain lysate, hippocampus and cortex. Furthermore, we compared protein expression patterns and regional changes at P80, P365 and P730. Ultimately, we determined the relative phosphorylation pattern of CaMKIIα and MAPK through quantification of neural p-CaMKIIα and p-MAPK/ErK, and IGF-1R expression for P80, P365 and P730 brain samples. In addition to a change in synaptic function, our results show a decrease in neural IGF-1/IGF-1R expression in whole brain, hippocampus and cortex of aged mice. This was associated with a significant upregulation of phosphorylated neural MAPK (p-MAPK) and decrease in total brain CaMKIIα (i.e., CaMKIIα and p-CaMKIIα) in the aged brain. Taken together, we showed that brain aging is associated with a change in neural IGF-1/IGF-1R expression and may be linked to a change in phosphorylation of synaptic kinases (CaMKIIα and MAPK) that are involved in the modulation of LTP.

Heme Oxygenase-1 and Brain Oxysterols Metabolism Are Linked to Egr-1 Expression in Aged Mice Cortex, but Not in Hippocampus

“…This result is in line with previous observations, although in mouse lung cells exposed to cigarette smoke, where Egr-1 was able to regulate HO-1 ( Chen et al, 2010 ). Finally, our data showed that this signaling may be sustained by the phosphorylation of ERK1/2 in the old brain cortex, which has already been described to be more activated during aging and to be associated to synaptic dysfunction ( Ogundele et al, 2018 ). Furthermore, in smooth muscle cells Egr-1 was demonstrated to be activated via ERK1/2 under OS conditions ( Pagel and Deindl, 2012 ).…”

Identification of the molecular mechanism of insulin-like growth factor-1 (IGF-1): a promising therapeutic target for neurodegenerative diseases associated with metabolic syndrome

“…Additionally, Bhat et al, reported that a high-fat/high-cholesterol diet can promote cognitive decline and brain dysfunction [ 156 ]. High fat diet (HFD)-induced obesity altered the circulating IGF cascade and increased circulatory level of total IGF-1, IGF-2, free IGF-1, and IGFBP3 in rodent and clinical trials [ 157 , 158 ]. However, insulin/IGF signaling (IIS) may be critical in diet-induced AD-like pathology.…”

“…There is a considerable increase in neural MAPK phosphorylation with aging along with a decrease in Calcium/Calmodulin-Dependent Protein Kinase IIa (CaMKIIa) levels. Changes in the phosphorylation of synaptic kinases (CaMKII and MAPK) involved in the regulation of long-term potentiation may be related to IGF-1/IGF-1R signalling [ 158 ]. IGF-1 was recently identified as belonging to a new class of ion channel modulators with rapid response (Fig.…”

IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis

“…Insulin-like growth factor type 1 receptor (IGF1R) is an important cellular modulator with essential roles in the regulation of growth, development and metabolism, as well as in cellular processes like proliferation, survival, cell migration and differentiation; affecting nearly every organ system in the body [ 1 , 2 , 3 ]. Belonging to the family of transmembrane receptor tyrosine kinases (RTKs), where it is also included its highly homologous insulin receptor (IR), IGF1R is a transmembrane heterotetrameric glycoprotein consisting of two extracellular α subunits containing the IGF-binding site and two intracellular β subunits that exhibit tyrosine kinase activity [ 4 ].…”