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Poly(I:C) promotes neurotoxic amyloid ß accumulation through reduced degradation by decreasing neprilysin protein levels in astrocytes.
Yamamoto, Naoki; Tokumon, Takuya; Obuchi, Ayako; Kono, Mari; Saigo, Katsuyasu; Tanida, Mamoru; Ikeda-Matsuo, Yuri; Sobue, Kazuya.
Affiliation
  • Yamamoto N; Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan.
  • Tokumon T; Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, Japan.
  • Obuchi A; Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, Japan.
  • Kono M; Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, Japan.
  • Saigo K; Scientific Research, Scientific Affairs, Sysmex Corporation, Kobe, Hyogo, Japan.
  • Tanida M; Faculty of Nursing, Himeji Dokkyo University, Himeji, Hyogo, Japan.
  • Ikeda-Matsuo Y; Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
  • Sobue K; Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, Japan.
J Neurochem ; 163(6): 517-530, 2022 12.
Article in En | MEDLINE | ID: mdl-36321194
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. Polyinosinicpolycytidylic acid (poly[IC]) 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 ß (Aß) in the brain of patients with AD is poorly understood. Neprilysin (NEP) and insulin-degrading enzyme (IDE) are the main Aß-degrading enzymes in the brain. This study investigated whether poly(IC) regulated Aß 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(IC) and inhibitors of the TLR3 signaling. Protein levels were assessed by Western blot. Aß toxicity to primary neurons was measured by lactate dehydrogenase release. Poly(IC) induced a significant decrease in NEP levels on the membrane of astrocytes as well as in the culture medium. The degradation of exogenous Aß was markedly delayed in poly(IC)-treated astrocytes. This delay significantly increased the neurotoxicity of exogenous Aß1-42. Altogether, these results suggest that viral infections induce Aß neurotoxicity by decreasing NEP levels in astrocytes and consequently preventing Aß degradation.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Virus Diseases / Neprilysin / Astrocytes / Amyloid beta-Peptides / Alzheimer Disease / Insulysin Limits: Animals Language: En Journal: J Neurochem Year: 2022 Document type: Article Affiliation country: Japón

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Virus Diseases / Neprilysin / Astrocytes / Amyloid beta-Peptides / Alzheimer Disease / Insulysin Limits: Animals Language: En Journal: J Neurochem Year: 2022 Document type: Article Affiliation country: Japón