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Pathogenic Role of RAGE in Tau Transmission and Memory Deficits.
Kim, Youbin; Park, Hyejin; Kim, Youngwon; Kim, Seo-Hyun; Lee, Jae Hoon; Yang, Hanseul; Kim, Seo Jin; Li, Cathena Meiling; Lee, Haneul; Na, Do-Hyeong; Moon, Seowon; Shin, Yumi; Kam, Tae-In; Lee, Han-Woong; Kim, SangYun; Song, Ji-Joon; Jung, Yong-Keun.
Afiliación
  • Kim Y; Interdisciplinary Program in Neuroscience, Seoul National University, Seoul, Republic of Korea; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Park H; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Kim Y; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Kim SH; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Lee JH; Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
  • Yang H; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Kim SJ; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Li CM; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Lee H; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Na DH; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Moon S; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea.
  • Shin Y; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • Kam TI; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Lee HW; Department of Biochemistry, Yonsei University, Seoul, Republic of Korea.
  • Kim S; Department of Neurology, Seoul National University Bundang Hospital and Seoul National University College of Medicine, Gyeonggi-do, Republic of Korea.
  • Song JJ; Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • Jung YK; Interdisciplinary Program in Neuroscience, Seoul National University, Seoul, Republic of Korea; School of the Biological Sciences, Seoul National University, Seoul, Republic of Korea. Electronic address: ykjung@snu.ac.kr.
Biol Psychiatry ; 93(9): 829-841, 2023 05 01.
Article en En | MEDLINE | ID: mdl-36759256
BACKGROUND: In tauopathies, brain regions with tau accumulation strongly correlate with clinical symptoms, and spreading of misfolded tau along neural network leads to disease progression. However, the underlying mechanisms by which tau proteins enter neurons during pathological propagation remain unclear. METHODS: To identify membrane receptors responsible for neuronal propagation of tau oligomers, we established a cell-based tau uptake assay and screened complementary DNA expression library. Tau uptake and propagation were analyzed in vitro and in vivo using a microfluidic device and stereotactic injection. The cognitive function of mice was assessed using behavioral tests. RESULTS: From a genome-wide cell-based functional screening, RAGE (receptor for advanced glycation end products) was isolated to stimulate the cellular uptake of tau oligomers. Rage deficiency reduced neuronal uptake of pathological tau prepared from rTg4510 mouse brains or cerebrospinal fluid from patients with Alzheimer's disease and slowed tau propagation between neurons cultured in a 3-chamber microfluidic device. RAGE levels were increased in the brains of rTg4510 mice and tau oligomer-treated neurons. Rage knockout decreased tau transmission in the brains of nontransgenic mice after injection with Alzheimer's disease patient-derived tau and ameliorated memory loss after injection with GFP-P301L-tau-AAV. Treatment of RAGE antagonist FPS-ZM1 blocked transsynaptic tau propagation and inflammatory responses and alleviated cognitive impairment in rTg4510 mice. CONCLUSIONS: These results suggest that in neurons and microglia, RAGE binds to pathological tau and facilitates neuronal tau pathology progression and behavioral deficits in tauopathies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Tauopatías / Enfermedad de Alzheimer / Receptor para Productos Finales de Glicación Avanzada Límite: Animals Idioma: En Revista: Biol Psychiatry Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Tauopatías / Enfermedad de Alzheimer / Receptor para Productos Finales de Glicación Avanzada Límite: Animals Idioma: En Revista: Biol Psychiatry Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos