Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus

Abstract

Aging is a multifactorial process associated with an increased susceptibility to neurodegenerative disorders which can be related to chronic inflammation. Chronic inflammation, however, can be characterized by the persistent elevated glucocorticoid (GCs) levels, activation of the proinflammatory transcription factor NF-кB, as well as an increase in cytokines. Interestingly, both NF-кB and cytokines can be even modulated by Glycogen Synthase Kinase 3 beta (GSK-3β) activity, which is a key protein that can intermediate inflammation and metabolism, once it has a critical role in AKT signaling pathway, and can also intermediate WNT/β-CATENIN signaling pathway. The aim of this study was to verify age-related changes in inflammatory status, as well as in the AKT and WNT signaling pathways. Results showed an age-related increase in neuroinflammation as indicated by NF-кB activation, TNF-α and GCs increased levels, a decrease in AKT activation and an increase in GSK-3β activity in both 12- and 24- month old animals. Aging also seems to induce a progressive decrease in canonical WNT/β-CATENIN signaling pathway once there is a decrease in DVL-2 levels and in the transcription of Axin2 gene. Little is known about the DVL-2 regulation as well as its roles in WNT signaling pathway, but for the first time it was suggested that DVL-2 expression can be changed along aging.

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…Furthermore, it was previously demonstrated that the mTOR inhibitor rapamycin has both antiepileptogenic effects (about 50% seizure development decrease vs 30% obtained with fingolimod) and some, albeit limited, anti-absence effects with longlasting antiepileptogenic effects [29,31]. Of note, we found an age-dependent increase in the phosphorylation of p-AKT in older control rats [68]; however, the significance of this result still remains controversial [69].…”

The role of the Wnt canonical signaling in neurodegenerative diseases

“…Recently, it was reported that neuroinflammation is a process age-related and correlated with increased GSK-3β and NF-кB activation and decreased Akt and Wnt/β-catenin function in the hippocampus of older rats [62]. Interestingly, it was found that the Wnt canonical pathway can modulate inflammatory responses also through the interaction with other signaling pathways.…”

The age factor in axonal repair after spinal cord injury: A focus on neuron-intrinsic mechanisms

“…Additionally, inactivation of the GSK3β-CRMP-2 pathway in dorsal root ganglion (DRG) neurons enhances axon regeneration via increasing microtubule dynamics in the growth cone [63]. Intriguingly, a decrease in p-Akt and p-GSK3β in the hippocampus has been reported in aged mice [78]. One interesting theory to test would be that in aged animals, a decrease of p-GSK3β results in regeneration decline, counterbalancing the regenerative effect of S6K1 activation following PTEN deletion.…”

“…However, contradictory results are found in the literature. Indeed, some studies reported a decrease in Wnt/β-catenin signaling in hippocampal cells of aged rats, which may be involved in a decline of neurogenesis with age [77, 78]. Additionally, Wnt deficiency is associated with another age-associated disease, Alzheimer disease [14].…”