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

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

doi:10.1016/j.neuron.2024.06.029

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

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 BanoÁdám Dénes, Eike Latz, Ronald Melki, Hans Christian Pape, Michael T. Heneka^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

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 (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.

Original language	English
Pages (from-to)	3106-3125.e8
Journal	Neuron
Volume	112
Issue number	18
Early online date	23 Jul 2024
DOIs	https://doi.org/10.1016/j.neuron.2024.06.029
Publication status	Published - 25 Sept 2024
Externally published	Yes

Keywords

alpha-synuclein
intercellular transfer
Lrrk2 G2019S
microglia
mitochondria
neurons
oxidative stress
tau
Trem2
tunneling nanotubes

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10.1016/j.neuron.2024.06.029Licence: CC BY-NC-ND

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Scheiblich, H., Eikens, F., Wischhof, L., Opitz, S., Jüngling, K., Cserép, C., Schmidt, S. V., Lambertz, J., Bellande, T., Pósfai, B., Geck, C., Spitzer, J., Odainic, A., Castro-Gomez, S., Schwartz, S., Boussaad, I., Krüger, R., Glaab, E., Di Monte, D. A., ... Heneka, M. T. (2024). Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes. Neuron, 112(18), 3106-3125.e8. https://doi.org/10.1016/j.neuron.2024.06.029

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title = "Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes",

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 (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.",

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author = "Hannah Scheiblich and Frederik Eikens and Lena Wischhof and Sabine Opitz and Kay J{\"u}ngling and Csaba Cser{\'e}p and Schmidt, {Susanne V.} and Jessica Lambertz and Tracy Bellande and Bal{\'a}zs P{\'o}sfai and Charlotte Geck and Jasper Spitzer and Alexandru Odainic and Sergio Castro-Gomez and Stephanie Schwartz and Ibrahim Boussaad and Rejko Kr{\"u}ger and Enrico Glaab and {Di Monte}, {Donato A.} and Daniele Bano and {\'A}d{\'a}m D{\'e}nes and Eike Latz and Ronald Melki and Pape, {Hans Christian} and Heneka, {Michael T.}",

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year = "2024",

month = sep,

day = "25",

doi = "10.1016/j.neuron.2024.06.029",

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Scheiblich, H, Eikens, F, Wischhof, L, Opitz, S, Jüngling, K, Cserép, C, Schmidt, SV, Lambertz, J, Bellande, T, Pósfai, B, Geck, C, Spitzer, J, Odainic, A, Castro-Gomez, S, Schwartz, S, Boussaad, I , Krüger, R, Glaab, E, Di Monte, DA, Bano, D, Dénes, Á, Latz, E, Melki, R, Pape, HC & Heneka, MT 2024, 'Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes', Neuron, vol. 112, no. 18, pp. 3106-3125.e8. https://doi.org/10.1016/j.neuron.2024.06.029

TY - JOUR

T1 - Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes

AU - Scheiblich, Hannah

AU - Eikens, Frederik

AU - Wischhof, Lena

AU - Opitz, Sabine

AU - Jüngling, Kay

AU - Cserép, Csaba

AU - Schmidt, Susanne V.

AU - Lambertz, Jessica

AU - Bellande, Tracy

AU - Pósfai, Balázs

AU - Geck, Charlotte

AU - Spitzer, Jasper

AU - Odainic, Alexandru

AU - Castro-Gomez, Sergio

AU - Schwartz, Stephanie

AU - Boussaad, Ibrahim

AU - Krüger, Rejko

AU - Glaab, Enrico

AU - Di Monte, Donato A.

AU - Bano, Daniele

AU - Dénes, Ádám

AU - Latz, Eike

AU - Melki, Ronald

AU - Pape, Hans Christian

AU - Heneka, Michael T.

PY - 2024/9/25

Y1 - 2024/9/25

N2 - 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.

AB - 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.

KW - alpha-synuclein

KW - intercellular transfer

KW - Lrrk2 G2019S

KW - microglia

KW - mitochondria

KW - neurons

KW - oxidative stress

KW - tau

KW - Trem2

KW - tunneling nanotubes

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UR - https://pubmed.ncbi.nlm.nih.gov/39059388/

U2 - 10.1016/j.neuron.2024.06.029

DO - 10.1016/j.neuron.2024.06.029

M3 - Article

C2 - 39059388

AN - SCOPUS:85200994889

SN - 0896-6273

VL - 112

SP - 3106-3125.e8

JO - Neuron

JF - Neuron

IS - 18

ER -

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

Abstract

Keywords

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