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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1421455

Erlotinib regulates short-term memory, tau/Aβ pathology, and astrogliosis in mouse models of AD

Provisionally accepted
Hyang-Sook Hoe Hyang-Sook Hoe *Hyun-ju Lee Hyun-ju Lee Jieun Kim Jieun Kim JinHee Park JinHee Park Jeong-Woo Hwang Jeong-Woo Hwang Yoo Joo Jeong Yoo Joo Jeong Ji-Yeong Jang Ji-Yeong Jang Su-Jeong Kim Su-Jeong Kim A-Ran Jo A-Ran Jo
  • Korea Brain Research Institute, Daegu, Republic of Korea

The final, formatted version of the article will be published soon.

    Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor that is approved by the FDA to treat non-small cell lung cancer (NSCLC). Several membrane receptors, including EGFR, interact with amyloid  (A), raising the possibility that erlotinib could have therapeutic effects on Alzheimer's disease (AD). However, the effects of erlotinib on Aβ/tau-related pathology and cognitive function in mouse models of AD and its mechanisms of action have not been examined in detail. In this study, we investigated the effects of erlotinib on cognitive function and found that erlotinib significantly enhanced short-term spatial memory and dendritic spine formation in 6-month-old P301S tau transgenic (PS19) mice. Importantly, erlotinib administration reduced tau phosphorylation at Ser202/Thr205 (AT8) and Thr231 (AT180) and further aggregation of tau into paired helical fragments (PHFs) and neurofibrillary tangles (NFTs) in 3-month-old and/or 6-month-old PS19 mice by suppressing the expression of the tau kinase DYRK1A. Moreover, erlotinib treatment decreased astrogliosis in 6-month-old PS19 mice and reduced proinflammatory responses in primary astrocytes (PACs) from PS19 mice. In 3- to 3.5-month-old 5xFAD mice, erlotinib treatment improved short-term spatial memory and hippocampal dendritic spine number and diminished Aβ plaque deposition and tau hyperphosphorylation. Furthermore, erlotinib-treated 5xFAD mice exhibited significant downregulation of astrocyte activation, and treating PACs from 5xFAD mice with erlotinib markedly reduced cxcl10 (reactive astrocyte marker) and gbp2 (A1 astrocyte marker) mRNA levels and proinflammatory cytokine mRNA and protein levels. Taken together, our results suggest that erlotinib regulates tau/Aβ-induced AD pathology, cognitive function, and Aβ/tau-evoked astrogliosis and therefore could be a potent therapeutic drug for ameliorating AD symptoms.

    Keywords: Alzheimer's disease, erlotinib, tau, Amyloid beta, DYRK1A, Astrogliosis

    Received: 22 Apr 2024; Accepted: 04 Sep 2024.

    Copyright: © 2024 Hoe, Lee, Kim, Park, Hwang, Jeong, Jang, Kim and Jo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Hyang-Sook Hoe, Korea Brain Research Institute, Daegu, Republic of Korea

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