Poly(I:C) promotes neurotoxic amyloid β accumulation through reduced degradation by decreasing neprilysin protein levels in astrocytes. Issue 6 (16th November 2022)

• Record Type: Journal Article
• Authors: Yamamoto, Naoki; Tokumon, Takuya; Obuchi, Ayako; Kono, Mari; Saigo, Katsuyasu; Tanida, Mamoru; Ikeda‐Matsuo, Yuri; Sobue, Kazuya
• Is Part Of: Journal of neurochemistry. Volume 163:Issue 6(2022)
• Page Start: 517
• Page End: 530
• Publication Date: 2022-11-16
• Subjects: Alzheimer's disease -- amyloid β -- astrocytes -- neprilysin -- poly(I:C) -- toll‐like receptor; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15716
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Inflammation associated with viral infection of the nervous system has been involved in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD) and multiple sclerosis. Polyinosinic:polycytidylic acid (poly[I:C]) is a Toll‐like receptor 3 (TLR3) agonist that mimics the inflammatory response to systemic viral infections. Despite growing recognition of the role of glial cells in AD pathology, their involvement in the accumulation and clearance of amyloid β (Aβ) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin‐degrading enzyme (IDE) are the main Aβ‐degrading enzymes in the brain. This study investigated whether poly(I:C) regulated Aβ degradation and neurotoxicity by modulating NEP and IDE protein levels through TLR3 in astrocytes. To this aim, primary rat primary astrocyte cultures were treated with poly(I:C) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aβ toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(I:C) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aβ was markedly delayed in poly(I:C)‐treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aβ1‐42. Altogether, these results suggest that viral infections induce Aβ neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aβ degradation. Abstract : Inflammation associated with viral infection of the nervous system is involved in the pathogenesis of Alzheimer's disease. Poly(I:C), mimics the inflammatory response to viral infections, reduced neprilysin protein levels through ERK1/2 signaling following TLR3 of astrocytes. Poly(I:C) delayed the Aβ degradation by reducing neprilysin protein levels of astrocytes. This delay on astrocytes increased the neurotoxicity of exogenous Aβ1–42. We indicate that viral infections induce Aβ neurotoxicity by decreasing NEP protein levels in astrocytes and consequently preventing Aβ degradation.