Aβ stimulates microglial activation through antizyme‐dependent downregulation of ornithine decarboxylase

Abstract

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. Its pathology is associated with the deposition of amyloid β (Aβ), an abnormal extracellular peptide. Moreover, its pathological progression is closely accompanied by neuroinflammation. Specifically, Aβ‐associated microglial overactivation may have the central role in AD pathogenesis. Interestingly, arginine metabolism may contribute to the equilibrium between M1 and M2 microglia. However, little is known about the involvement of arginine metabolism in Aβ‐induced microglial neuroinflammation and neurotoxicity. Moreover, the underlying mechanism by which Aβ induces the transition of microglia to the M1 phenotype remains unclear. In this study, we investigated the role of Aβ in mediating microglial activation and polarization both in vitro and in vivo. Our results demonstrated that under the Aβ treatment, ornithine decarboxylase (ODC), a rate‐limiting enzyme in the regulation of arginine catabolism, regulates microglial activation by altering the antizyme (AZ) + 1 ribosomal frameshift. Furthermore, the restoration of ODC protein expression levels has profound effects on inhibition of Aβ‐induced M1 markers and thus attenuates microglial‐mediated cytotoxicity. Altogether, our findings suggested that Aβ may contribute to M1‐like activation by disrupting the balance between ODC and AZ in microglia.

Microglia: Agents of the CNS Pro-Inflammatory Response

“…Arginine metabolism has been reported to play a key role in immunometabolic responses in microglia [331][332][333]. The current evidence suggests two alternative and competitive directions for arginine: Into the NO synthesis pathway associated with the inflammatory response or into the arginase pathway associated with wound healing and repair [334,335].…”

Activated microglia-induced neuroinflammatory cytokines lead to photoreceptor apoptosis in age-related macular degeneration-like mice model

“…42 treated group, such as IL-1β, COX-2, TNF-α and iNOS, were dramatically increased, which was about 5.1-, 6.1-, 3.2-, and 2.7-fold, respectively, of that in control. BIRB 796 largely abolished such increases and phosphorylated p38 MAPK protein level decreased in Aβ 1−42 induced microglia cultures correspondingly(Fig.…”

“…Aβ 1−42 oligomeric peptide (Sigma-Aldrich Company, Germany, Catalog Number A9810) was dissolved with anhydrous dimethyl sulfoxide (DMSO) to the concentration 500 µmol/L as previous described [42]. And then the stock solution (100 µmol/L) was make phosphate-buffered saline (PBS) and stored at − 20 °C before use.…”

Cerebralcare Granule® enhances memantine hydrochloride efficacy in APP/PS1 mice by ameliorating amyloid pathology and cognitive functions

“…Some researchers have suggested that Aβ disturbs the oxidative balance by causing mitochondrial dysfunction and lipid peroxidation to enhance oxidative stress [ 50 ]. In addition, glial cells can be over-activated by Aβ to release inflammatory factors to form a chronic neuroinflammatory environment in the brain [ 51 ]. Therefore, anti-inflammatory and anti-oxidative treatments are beneficial to AD.…”