Glia maturation factor modulates β-amyloid-induced glial activation, inflammatory cytokine/chemokine production and neuronal damage

Abstract

Glia maturation factor (GMF), discovered and characterized in our laboratory, is a highly conserved protein primarily localized in mammalian central nervous system. Previously we demonstrated that GMF is required in the induced production of proinflammatory cytokines and chemokines in brain cells. We now report that ventricular infusion of human amyloid beta peptide1-42 (Abeta1-42) in mouse brain caused glial activation and large increases in the levels of GMF as well as induction of inflammatory cytokine/chemokine known for launching the neuro inflammatory cascade in Alzheimer's disease (AD). To test the hypothesis that GMF is involved in the pathogenesis of AD, we infused Abeta1-42 in the brain of GMF-deficient (GMF-KO) mice, recently prepared in our laboratory. GMF-deficient mice showed reduced glial activation and significantly suppressed proinflammatory cytokine/chemokine production following Abeta infusion compared to wild type (Wt) mice. The decrease in glial activation in the GMF-KO mice is also associated with significant reduction in Abeta induced loss of pre-synaptic marker, synaptophysin, and post-synaptic density protein-95 (PSD 95). We also examined the potential relationship between GMF or lack of it with learning and memory using the T-maze, Y-maze, and water maze, hippocampal-dependent spatial memory tasks. Our results show that memory retention was improved in GMF-KO mice compared to Wt controls following Abeta infusion. Diminution of these Abeta1-42 effects in primary cultures of GMF-KO astrocyte and microglia were reversed by reconstituted expression of GMF. Taken together, our results indicate a novel mediatory role of GMF in the neuro-inflammatory pathway of Abeta and its pro-inflammatory functions.

Protection of PMS777, a New AChE Inhibitor with PAF Antagonism, Against Amyloid-β-Induced Neuronal Apoptosis and Neuroinflammation

“…Several in vitro studies have demonstrated that Ab might function as an immune stimulus for microglia or astrocyte activation and lead to neuroinflammation in the brain of AD patients or animals (Meda et al 1995;MiguelHidalgo et al 2002;Zaheer et al 2008). Consistently, the present study showed that unilateral hippocampal injection of Ab resulted in obvious inflammatory responses, manifested as the significant increase in markers of astrocytic and microglial activation.…”

“…Abinduced neurotoxicity, which leads to the selective cholinergic neuronal apoptosis, involves multiple mechanisms. Besides direct neuronal damage, excitotoxicity and oxidative stress, Ab can function as an immune stimulus for glial activation and evoke chronic neuroinflammation in brain of AD patients or animals (Meda et al 1995;Miguel-Hidalgo et al 2002;Zaheer et al 2008). Therefore, enhancement of acetylcholine (ACh) concentration by inhibiting acetylcholinesterase (AChE) activity or blockade of the neuroinflammation by inhibiting the action of proinflammatory mediators has been regarded as important strategies for AD therapy.…”

Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies

“…receptor for advanced glycosylation endproducts (RAGE), NOD-, LRR-and pyrin domain-containing 3 (NLRP3)), microglia are activated, leading to the production of cytokines (e.g. interleukin (IL)-1b, IL-6, IL-8, tumor necrosis factor-a (TNF-a), chemokines, and nitrogen species, which damage neurons; Zaheer et al, 2008). This proinflammatory response is sustained over time and can cause neuronal death, which in turn, overactivates microglia, in a cycle termed reactive microgliosis.…”

MicroRNA-139 modulates Alzheimer’s-associated pathogenesis in SAMP8 mice by targeting cannabinoid receptor type 2

“…Microglia activated in vitro induce the expression of proinflammatory cytokines, including IL-6, IL-8, TNF-a, reactive oxygen/nitrogen species, and chemokines, all of which are known to cause neuronal damage (Van Eldik et al, 2007;Zaheer et al, 2008;Fernández et al, 2013). Studies on brain tissue derived from patients with AD have shown that CB2 modulates hippocampal function in the context of AD pathology (Benito et al, 2003).…”