Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion

Abstract

Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH.

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

“…Accordingly to our model, Glpr2 decreases by 90% in vascular dementia as compared to controls (Fig. 7J and Supplementary Table 9) suggesting ongoing vascular hypoxia ((Xie et al 2018)). On the other hand, the inflammatory and vascular markers, Lcn2, Cyp1b1, increase in the vascular dementia as in the PP model ( Fig.…”

“…Investigating the genes involved in mediating vascular function (Deniz, Bozkurt, and Kurtel 2007), we observe no change in Glpr2 expression in the progression of AD, while in VaD, Glpr2 is downregulated similarly to the PP model supporting that cognitive deficit is contributed by lower blood perfusion ((Xie et al 2018)). Along the same lines, the progressive increase in the inflammatory and metabolic markers, Lcn2, displayed by aging PP animals, is not reproduced in AD but in the VaD specimen.…”

“…Finally, Plin4 and Lcn2 are positively associated with their increasing trend from 9 to 16 months, confirming the RNAseq data and supporting the subsequent investigation of these neuroinflammatory markers in aged PP mice. Based on downregulation of Glpr2 in adulthood, indicating vascular hyperperfusion (Xie et al 2018) and the subsequent upregulation of the vascular and inflammatory markers, Lcn-2, at 9 months, we investigated vascular integrity by validating the gene expression of Kruppel-like factor 4, Klf-4, at 9 and 16 months and observed a transient downregulation at 9 months (Table 2). At the same time point, angiogenesis markers such as Cytochrome P450 Family 1 Subfamily B Member 1, Cyp1b1, and Angiopoietin-like 4, Angptl4, with reported function in vascular AD and homeostasis (Chakraborty et al 2018;Ghosh et al 2016) showed a peak at 9 months, supporting pathological vascular processes in aged adult PP mice.…”

Systemic Inflammation Causes Microglial Dysfunction with a Mixed AD-Like Pathology.

“…This mechanistic progression is theoretically confirmed by an aggregate GEA using KEGG, Wikipathway and Reactome pathways, which shows an early abundance in calcium signaling cascades, inflammation pathways, including MAPK signaling, PI3K-AKT signaling associated to cell survival and apoptosis. While at 6 months we confirmed an important decrease in Glpr2 associated to synaptic depotentiation in response to hyperactivity (Sasaki-Hamada, Ikeda, and Oka 2019), (Xie et al 2018;Bhusal et al 2019), the changes in gene expression are much pronounced in the midaged 9 months and older 16 months PP mice with a 10% gene overlap. Longitudinal characterization revealed the upregulation of three genes (Plin4, H2-Aa, Lcn2) related to proinflammatory and glial function and downregulation of three genes (Jun, Egr2, Kcnj2) linked to neuronal or ion transport, reinforcing the mechanisms occurring in the progression of the neuropathology.…”

“…As expected at this stage, Plin4 and Egr2 are unchanged, matching the RNAseq data (Table 2). At 6 months, we analyzed one of the genes with the strongest downregulation at the RNA-seq, with reported association with cognitive impairment in chronic cerebral hypoperfusion (Xie et al 2018). The Glpr2 (Glucagon-Like Peptide 2 Receptor) decrease (80%), is confirmed (Table 2; p<0.05).…”