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Harvard Medical School

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Neuron, Aug 30 2023, S0896-6273(23)00623-2 | https://doi.org/10.1016/j.neuron.2023.08.012 Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling.

Eunhee Kim ¹, Hyeonwoo Kim ², Mark P Jedrychowski ³, Grisilda Bakiasi ¹, Joseph Park ¹, Jane Kruskop ¹, Younjung Choi ¹, Sang Su Kwak ¹, Luisa Quinti ¹, Doo Yeon Kim ¹, Christiane D Wrann ⁴, Bruce M Spiegelman ³, Rudolph E Tanzi ^{5 *}, Se Hoon Choi^{6 *}

¹Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
²Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA; Department of Biological Sciences, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 34141, Republic of Korea.
³Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA.
⁴McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
⁵Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.

^*Corresponding author: correspondence to Rudolph E Tanzi or Se Hoon Choi

Abstract

A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aβ pathology by increasing astrocytic release of the Aβ-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, we show that integrin αV/β5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aβ. Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aβ pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD.

논문정보

형식Research article
게재일2023년 08월 (BRIC 등록일 2023-09-11)
연구진국내+국외 연구진
분야 의약학 > 신경의학

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