Anle138b mitigates post-hypoxic cognitive impairment, α-Synuclein aggregation and UPR activation in Drosophila melanogaster

Acta Neuropathologica Communications, vol. 13, pp. 230

Abstract

Cerebral ischemia increases the risk of post-stroke cognitive impairment (PSCI), but the underlying molecular mechanisms remain unclear. Emerging evidence suggests that hypoxia/ischemia-induced oxidative and endoplasmic reticulum (ER) stress may contribute to protein misfolding and α-Synuclein (α-Syn) aggregation, potentially triggering the unfolded protein response (UPR) to alleviate ER stress. Using bimolecular fluorescence complementation in Drosophila melanogaster and HEK-293 cells, we investigated the effect of acute, repetitive and chronic hypoxia on α-Syn aggregation, UPR activation, mortality, longevity, locomotor function, sleep, and cognition. Furthermore, we evaluated the post-hypoxic in vivo biodistribution and therapeutic efficacy of the aggregation inhibitor anle138b. Acute severe hypoxia induced more α-Syn aggregation than chronic or repetitive hypoxia, resulting in higher mortality, reduced longevity, delayed motor recovery, cognitive impairment, and activation of the detrimental PERK branch of the UPR. Anle138b significantly reduced α-Syn aggregation, repressing post-hypoxic PERK activation and improving survival and decision-making. Our findings demonstrate the effectiveness of anle138b in mitigating hypoxia-induced α-Syn aggregation and cognitive impairment, paving the way for future studies on its potential as a therapeutic strategy for PSCI.

Authors 10

1. Aaron T. Fehr Aachen Department of Neurology, Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

2. Jennifer Jung Aachen Department of Neurology, Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

3. Alma Kokott-Vuong Aachen Department of Neurology, Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

4. Sabri E. M. Sahnoun Aachen Department of Nuclear Medicine

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074, Aachen, Germany

5. Aya A. Ezzat Aachen Department of Nuclear Medicine

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074, Aachen, Germany

6. Michael Huber Aachen Institute of Biochemistry and Molecular Immunology Medical Faculty

   RWTH Aachen University

   Affiliation as printed

   Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

7. Tonya M. Bliss

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA

8. Aaron Voigt Aachen Department of Neurology, Medical Faculty JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   Forschungszentrum Jülich · Jülich Aachen Research Alliance · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

   JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, 52074, Aachen, Germany

9. Jörg Bernhard Schulz Aachen Department of Neurology, Medical Faculty JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

   Forschungszentrum Jülich · Jülich Aachen Research Alliance · RWTH Aachen University

   Affiliation as printed

   Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany

   JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, 52074, Aachen, Germany

10. Pardes Habib corresponding Aachen Department of Neurology, Medical Faculty JARA Brain Institute Molecular Neuroscience and Neuroimaging (INM-11)

    Forschungszentrum Jülich · Jülich Aachen Research Alliance · Stanford Medicine · RWTH Aachen University · Stanford University

    Affiliation as printed

    Department of Neurology, Medical Faculty, RWTH Aachen University, 52074, Aachen, Germany. phabib@stanford.edu

    Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA. phabib@stanford.edu

    JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, 52074, Aachen, Germany. phabib@stanford.edu

    Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA

    JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, 52074, Aachen, Germany