Glial cell reactivity and oxidative stress prevention in Alzheimer’s disease mice model by an optimized NMDA receptor antagonist

Abstract

In Alzheimer's disease pathology, several neuronal processes are dysregulated by excitotoxicity including neuroinflammation and oxidative stress (OS). New therapeutic agents capable of modulating such processes are needed to foster neuroprotection. Here, the effect of an optimised NMDA receptor antagonist, UB-ALT-EV and memantine, as a gold standard, have been evaluated in 5XFAD mice. Following treatment with UB-ALT-EV, nor memantine, changes in the calcineurin (CaN)/NFAT pathway were detected. UB-ALT-EV increased neurotropic factors (Bdnf, Vgf and Ngf) gene expression. Treatments reduced astrocytic and microglial reactivity as revealed by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) quantification. Interestingly, only UB-ALT-EV was able to reduce gene expression of Trem2, a marker of microglial activation and NF-κB. Pro-inflammatory cytokines Il-1β, Ifn-γ, Ccl2 and Ccl3 were down-regulated in UB-ALT-EV-treated mice but not in memantine-treated mice. Interestingly, the anti-inflammatory markers of the M2-migroglial phenotype, chitinase-like 3 (Ym1) and Arginase-1(Arg1), were up-regulated after treatment with UB-ALT-EV. Since iNOS gene expression decreased after UB-ALT-EV treatment, a qPCR array containing 84 OS-related genes was performed. We found changes in Il-19, Il-22, Gpx6, Ncf1, Aox1 and Vim gene expression after UB-ALT-EV. Hence, our results reveal a robust effect on neuroinflammation and OS processes after UB-ALT-EV treatment, surpassing the memantine effect in 5XFAD.

Research trends and hotspots of glial fibrillary acidic protein within the area of Alzheimer’s disease: a bibliometric analysis

“…Since astrocytes and microglia could release proinflammatory cytokines and reactive oxygen, triggering neuroinflammation and oxidative stress ( Novoa et al, 2022 ), it is not surprising that “inflammation,” “neuroinflammation,” and “oxidative stress” were hot keywords related to GFAP, which is an important biomarker for astrocyte activation. Moreover, the inflammatory response, oxidative stress, and glial activation (especially microglia and astrocytes) have been found as three main factors for AD progression based on both mouse models and human post-mortem brains ( Companys-Alemany et al, 2022 ; Viejo et al, 2022 ). Furthermore, Aβ and tau are found able to activate astrocytes and microglia, and GFAP expression and protein concentrations were higher in areas surrounding dense Aβ plaques and increased with tau accumulation, implying the association of GFAP with amyloid and tau pathology ( Simpson et al, 2010 ; Novoa et al, 2022 ).…”

Deletion of Gadd45a Expression in Mice Leads to Cognitive and Synaptic Impairment Associated with Alzheimer’s Disease Hallmarks

“…Trem2 is a cell surface receptor expressed in microglia cells, iNOS is an enzyme that releases several inflammatory mediators and generates reactive oxygen species, and Tnf- α and IL-1β are cytokines required for activating the innate immune response. Therefore, all of the themes produce neuroinflammation followed by neuronal damage and AD progression [ 43 , 44 , 45 ]. Here, we showed that these genes were increased in KO animals.…”

Modulation of GPER1 alleviates early brain injury via inhibition of A1 reactive astrocytes activation after intracerebral hemorrhage in mice

“…On the one hand, activated astrocytes could play a protective effect through restricting injury by the formation of glia scar at acute phase of insult [ 33 ]. On the other hand, activated astrocytes have been verified to play a harmful effect via eliciting inflammatory cascade, oxidative stress and glutamate excitotoxicity [ [34] , [35] , [36] ]. Emerging evidence shows reactive astrocytes could be polarized to two opposite phenotypes, A1, the neurotoxic type which produce pro-inflammatory factors, and A2, the neuroprotective type, produce anti-inflammatory factors and neurotrophic factors [ 12 , 14 ].…”