AVE 0991 Suppresses Astrocyte-Mediated Neuroinflammation of Alzheimer’s Disease by Enhancing Autophagy

Abstract

Purpose Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimer’s disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimer’s disease. Materials and Methods APP/PS1 mice and Aβ-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aβ in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. Results We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aβ deposition, neuronal death, and cognitive deficits in APP/PS1 Alzheimer’s disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. Conclusion These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

EZH2 Methyltransferase Regulates Neuroinflammation and Neuropathic Pain

“…Autophagy is essential for cellular differentiation, homeostasis, and survival [ 91 , 92 ] and is conserved across evolution. Recent studies have shown that altered autophagy is involved in neuroinflammation processes in many neurological diseases, including Parkinson’s disease [ 93 , 94 ], Alzheimer’s disease [ 95 , 96 ], and neuropathic pain [ 67 , 97 , 98 ]. It was reported that autophagic activity in microglia in the spinal cord was suppressed in animals with neuropathic pain from day 2 to day 28 after nerve injury [ 99 ].…”

Fluvoxamine maleate ameliorates Alzheimer disease pathology by mitigating amyloid-beta load and neuroinflammation in 5XFAD mice

“…Therefore, autophagy has emerged as one of the most important mechanisms that regulate NLRP3 inflammasome [15,16]. Some recent studies have shown that induction of autophagy by pharmacological or non-pharmacological means can help mitigate NLRP3 inflammasome mediated or other types of inflammation [17][18][19][20]. Therefore, targeting NLRP3 inflammasome and autophagy together can be a good strategy, particularly when most of the monotargeted therapies have not shown any significant clinical advantage for treating AD.…”