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

Scheiblich, Hannah and Eikens, Frederik and Wischhof, Lena and Opitz, Sabine and Jüngling, Kay and Cserép, Csaba and Schmidt, Susanne V. and Lambertz, Jessica and Bellande, Tracy and Pósfai, Balázs and Geck, Charlotte and Spitzer, Jasper and Odainic, Alexandru and Castro-Gomez, Sergio and Schwartz, Stephanie and Boussaad, Ibrahim and Krüger, Rejko and Glaab, Enrico and Di Monte, Donato A. and Bano, Daniele and Dénes, Ádám and Latz, Eike and Melki, Ronald and Pape, Hans-Christian and Heneka, Michael T. (2024) Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. NEURON. ISSN 0896-6273 (In Press)

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Abstract

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 (a-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 a-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.

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