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

• DOI: 10.1016/j.neuron.2024.06.029
• Publication Date: 2024-07-25T15:45:58Z
• Authors: Hannah Scheiblich; Frederik Eikens; Lena Wischhof; Sabine Opitz; Kay Jüngling; Csaba Cserép; Susanne V. Schmidt; Jessica Lambertz; Tracy Bellande; Balázs Pósfai; Charlotte Geck; Jasper Spitzer; Alexandru Odainic; Sergio Castro-Gomez; Stephanie Schwartz; Ibrahim Boussaad; Rejko Krüger; Enrico Glaab; Donato A. Di Monte; Daniele Bano; Ádám Dénes; Eike Latz; Ronald Melki; Hans-Christian Pape; Michael T. Heneka
• Keywords: QD Chemistry / kémia; [SDV]Life Sciences [q-bio]; alpha-synuclein; metabolism [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2]; microglia; neurons; Cell Communication; QR Microbiology / mikrobiológia; metabolism [Microglia]; drug effects [Microglia]; physiology [Cell Death]; physiology [Oxidative Stress]; Tunneling Nanotubes; tunneling nanotubes; Mice; R1 Medicine (General) / orvostudomány általában; oxidative stress; metabolism [alpha-Synuclein]; tau; Cells, Cultured; Neurons; Nanotubes; QH3011 Biochemistry / biokémia; Cell Death; drug effects [Cell Communication]; drug effects [Mitochondria]; Lrrk2 G2019S; Mitochondria; mitochondria; metabolism [Neurons]; genetics [alpha-Synuclein]; alpha-Synuclein; drug effects [Oxidative Stress]; Microglia; Trem2; 570; 610; tau Proteins; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Cell Membrane Structures; drug effects [Neurons]; Animals; Humans; ddc:610; QH301 Biology / biológia; drug effects [Cell Death]; metabolism [Mitochondria]; intercellular transfer; metabolism [tau Proteins]; Coculture Techniques; genetics [tau Proteins]; Oxidative Stress; physiology [Cell Communication]; genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2]

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.