Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.

Autor:	Scheiblich H; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Bonn, Germany; Max-Planck-Institute for Biology of Ageing, Cologne, Germany., Eikens F; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Bonn, Germany; Max-Planck-Institute for Biology of Ageing, Cologne, Germany., Wischhof L; German Center for Neurodegenerative Diseases, Bonn, Germany; Max-Planck-Institute for Biology of Ageing, Cologne, Germany., Opitz S; Institute of Neuropathology, University of Bonn, Bonn, Germany., Jüngling K; Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany., Cserép C; Institute of Experimental Medicine, Budapest, Hungary., Schmidt SV; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Lambertz J; Institute of Anatomy, University Hospital Bonn, Bonn, Germany., Bellande T; Institut François Jacob, CEA and Laboratory of Neurodegenerative Diseases, Fontenay-aux-Roses, France., Pósfai B; Institute of Experimental Medicine, Budapest, Hungary., Geck C; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Spitzer J; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany., Odainic A; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection & Immunity, University of Melbourne, Melbourne, VIC, Australia., Castro-Gomez S; Institute of Physiology II, University Hospital Bonn, Bonn, Germany., Schwartz S; Institute of Physiology II, University Hospital Bonn, Bonn, Germany., Boussaad I; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Krüger R; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Glaab E; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg., Di Monte DA; German Center for Neurodegenerative Diseases, Bonn, Germany., Bano D; German Center for Neurodegenerative Diseases, Bonn, Germany., Dénes Á; Institute of Experimental Medicine, Budapest, Hungary., Latz E; German Center for Neurodegenerative Diseases, Bonn, Germany; Institute of innate immunity, University Hospital Bonn, Bonn, Germany., Melki R; Institut François Jacob, CEA and Laboratory of Neurodegenerative Diseases, Fontenay-aux-Roses, France., Pape HC; Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany., Heneka MT; German Center for Neurodegenerative Diseases, Bonn, Germany; Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg; Institute of innate immunity, University Hospital Bonn, Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts, Medical School, Worcester, MA, USA. Electronic address: michael.heneka@uni.lu.
Jazyk:	angličtina
Zdroj:	Neuron [Neuron] 2024 Sep 25; Vol. 112 (18), pp. 3106-3125.e8. Date of Electronic Publication: 2024 Jul 25.
DOI:	10.1016/j.neuron.2024.06.029
Abstrakt:	Microglia are crucial for maintaining brain health and neuron function. Here, we report that microglia establish connections with neurons using tunneling nanotubes (TNTs) in both physiological and pathological conditions. These TNTs facilitate the rapid exchange of organelles, vesicles, and proteins. In neurodegenerative diseases like Parkinson's and Alzheimer's disease, toxic aggregates of alpha-synuclein (α-syn) and tau accumulate within neurons. Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health. Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression. Disrupting mitochondrial function with antimycin A before TNT formation eliminates this neuroprotection. Moreover, co-culturing neurons with microglia and promoting TNT formation rescues suppressed neuronal activity caused by α-syn or tau aggregates. Notably, TNT-mediated aggregate transfer is compromised in microglia carrying Lrrk22(Gly2019Ser) or Trem2(T66M) and (R47H) mutations, suggesting a role in the pathology of these gene variants in neurodegenerative diseases. Competing Interests: Declaration of interests E.L. is a co-founder and advisor at IFM Therapeutics, and M.T.H. serves as an advisory board member at IFM Therapeutics, T3D, and Alector. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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