Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides.

Autor: Hanbouch L; Paris Brain Institute, ICM, CNRS UMR7225-INSERM U1127-Sorbonne University Hôpital de La Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France., Schaack B; Univ. Grenoble Alpes, CNRS, INP, TheRex Team, TIMC-IMAG, 38700, La Tronche, France.; Univ. Grenoble Alpes, CEA, CNRS, IBS, 38044, Grenoble, France., Kasri A; Paris Brain Institute, ICM, CNRS UMR7225-INSERM U1127-Sorbonne University Hôpital de La Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France., Fontaine G; Paris Brain Institute, ICM, CNRS UMR7225-INSERM U1127-Sorbonne University Hôpital de La Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France., Gkanatsiou E; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden., Brinkmalm G; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden., Camporesi E; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden., Portelius E; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden., Blennow K; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden., Mourier G; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.; Département Médicaments Et Technologies Pour La Santé (DMTS), Université Paris Saclay, CEA, INRAE, SIMoS, 91191, Gif-sur-Yvette, France., Gilles N; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.; Département Médicaments Et Technologies Pour La Santé (DMTS), Université Paris Saclay, CEA, INRAE, SIMoS, 91191, Gif-sur-Yvette, France., Millan MJ; Neuroscience Inflammation Thérapeutic Area, IDR Servier, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France.; Institute of Neuroscience and Psychology, College of Medicine, Vet and Life Sciences, Glasgow University, 62 Hillhead Street, Glasgow, G12 8QB, Scotland., Marquer C; Paris Brain Institute, ICM, CNRS UMR7225-INSERM U1127-Sorbonne University Hôpital de La Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France., Zetterberg H; Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, S-431 80, Sweden.; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, S-431 80, Mölndal, Sweden.; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK.; UK Dementia Research Institute at UCL, London, WC1E 6BT, UK., Boussicault L; Paris Brain Institute, ICM, CNRS UMR7225-INSERM U1127-Sorbonne University Hôpital de La Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France., Potier MC; Paris Brain Institute, ICM, CNRS UMR7225-INSERM U1127-Sorbonne University Hôpital de La Pitié-Salpêtrière, 47 Bd de l'Hôpital, 75013, Paris, France. marie-claude.potier@upmc.fr.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2022 Nov; Vol. 59 (11), pp. 7056-7073. Date of Electronic Publication: 2022 Sep 09.
DOI: 10.1007/s12035-022-03025-9
Abstrakt: Excess brain cholesterol is strongly implicated in the pathogenesis of Alzheimer's disease (AD). Here we evaluated how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of the amyloid precursor protein (APP) regulates its processing. We generated nine point mutations in the APP gene, changing the charge and/or hydrophobicity of the amino-acids which were previously shown as part of the CBS. Most mutations triggered a reduction of amyloid-β peptides Aβ40 and Aβ42 secretion from transiently transfected HEK293T cells. Only the mutations at position 28 of Aβ in the APP sequence resulted in a concomitant significant increase in the production of shorter Aβ peptides. Mass spectrometry (MS) confirmed the predominance of Aβx-33 and Aβx-34 with the APP K28A mutant. The enzymatic activity of α-, β-, and γ-secretases remained unchanged in cells expressing all mutants. Similarly, subcellular localization of the mutants in early endosomes did not differ from the APP WT protein. A transient increase of plasma membrane cholesterol enhanced the production of Aβ40 and Aβ42 by APP WT , an effect absent in APP K28A mutant. Finally, WT but not CBS mutant Aβ derived peptides bound to cholesterol-rich exosomes. Collectively, the present data revealed a major role of juxtamembrane amino acids of the APP CBS in modulating the production of toxic Aβ species. More generally, they underpin the role of cholesterol in the pathophysiology of AD.
(© 2022. The Author(s).)
Databáze: MEDLINE
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