Pathogenic Role of RAGE in Tau Transmission and Memory Deficits

Youbin Kim, Hyejin Park, Youngwon Kim, Seo Hyun Kim, Jae Hoon Lee, Hanseul Yang, Seo Jin Kim, Cathena Meiling Li, Haneul Lee, Do Hyeong Na, Seowon Moon, Yumi Shin, Tae In Kam, Han Woong Lee, Sang Yun Kim, Ji Joon Song, Yong Keun Jung

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)829-841
Number of pages13
JournalBiological psychiatry
Volume93
Issue number9
DOIs
StatePublished - May 1 2023

Keywords

  • Alzheimer's disease
  • FPS-ZM1
  • Memory loss
  • RAGE
  • Tau propagation

ASJC Scopus subject areas

  • Biological Psychiatry

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