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APP96-110 Elicits Neuroprotective Effects Following Ischemic Insult in Animal Models

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Abstract

Competitive amyloidogenic pathways play an important role in many neurological diseases such as the onset of various degenerative diseases and ischemic stroke. Overexpression of amyloid precursor protein (APP) and amyloid-beta is modulated via the amyloidogenic pathway, which plays a crucial role in neuroinflammation. During ischemic conditions, the activity of the anti-inflammatory non-amyloidogenic pathway decreases, thus increasing the activity of amyloidogenic pathway. The soluble alpha form of APP (sAPPα), formed via the non-amyloidogenic pathway, exhibits neuroprotective effects against neurological diseases. sAPPα is thought to have a modulatory effect on several cell survival pathways, including its ability to inhibit the phosphoinositide 3-kinases (PI3K) pathway, thereby inhibiting the inflammatory response. The APP derivative, APP96-110, could act as a functional substitute for native sAPPα. Herein, we investigated whether APP96-110 has neuroprotective effects against neuroinflammation and damage following cerebral ischemic stroke. Treatment with diluted APP96-110 (0.005 mg/kg) in mice after 30 min of transient middle cerebral artery occlusion (tMCAO) showed improved motor function and reduced expression of the inflammatory marker CD86. APP96-110 decreased the infarct size and induced an anti-inflammatory response by inhibiting the PI3K pathway. These results suggest that the treatment of APP96-110 is efficacious in reducing neuroinflammation and infarct size in ischemic stroke.

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Data availability

All datasets generated or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Editage (www.editage.co.kr) for English language editing.

Funding

This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF 780 2021R1A2C2008034 to JEL).

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Authors and Affiliations

  1. Department of Anatomy, Yonsei University College of Medicine, Seoul, 03722, South Korea

    Renée Kosonen, Ji Young Chang, Seowoo Lee, Jiwon Kim, Jong Youl Kim & Jong Eun Lee

  2. Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea

    Renée Kosonen, Ji Young Chang, Seowoo Lee, Jiwon Kim & Jong Eun Lee

  3. Brain Research Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea

    Jong Eun Lee

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  1. Renée Kosonen
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Contributions

Conceptualization of this study was performed by RK and JEL. Materials, preparation, data collection, and analyses were performed by RK, JYC, SWL, and JK. The first draft of this manuscript was written by RK. RK, JYK, and JEL commented on the previous versions of the manuscript. All authors contributed to this article and approved this submission.

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Correspondence to Jong Eun Lee.

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Kosonen, R., Chang, J.Y., Lee, S. et al. APP96-110 Elicits Neuroprotective Effects Following Ischemic Insult in Animal Models. Neurochem Res 48, 2568–2579 (2023). https://doi.org/10.1007/s11064-023-03928-6

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