The brain comprises various cell types, prominently featuring neurons and the lesser-known microglia. The microglia are essential components of the brain’s immune system, acting as the cleanup crew. A recent study sheds light on how microglia link with neurons through structures known as tunneling nanotubes. Researchers found that microglia use these tubes to help eliminate toxic proteins from neurons, thereby supporting neuronal well-being.
The buildup of harmful proteins is a signature of many neurodegenerative diseases, such as Alzheimer’s, frontotemporal dementia, and Parkinson’s disease. Proteins like alpha-synuclein and tau can form abnormal aggregates within neurons, disrupting their fundamental functions. “While we understood that microglia contribute to removing these protein aggregates, it was only recently that we recognized their ability to create tunneling nanotubes, which are long extensions connecting distant brain cells,” says Prof. Michael Heneka, director of the LCSB, head of the Neuroinflammation group, and the study’s lead author. “Our goal with this research was to further investigate how material is exchanged between neurons and microglia through these nanotubes and to understand the implications for cellular health.”
The research involved neuron and microglia cultures sourced from mouse models or human stem cells, utilizing advanced imaging techniques to showcase how microglia connect with neurons via tunneling nanotubes (TNTs) to alleviate toxic protein loads. Moreover, microglia aid distressed neurons by transferring healthy mitochondria—the cells’ energy generators—thereby significantly decreasing oxidative stress, restoring crucial functions, and ultimately saving those nerve cells.
Observing Tunneling Nanotubes Live
Through live cell imaging microscopy, the team witnessed the establishment of connections between neurons and microglia.
“Further investigation is required to fully understand how TNTs are formed and their functionality, but it was exciting to see microglia actively working to maintain neuronal health and extending support during critical periods,” notes Dr. Hannah Scheiblich, the study’s first author who collaborated with Prof. Heneka at the University Hospital Bonn and the German Center for Neurodegenerative Diseases.
Microglia Aid Neurons by Eliminating Proteins and Providing Mitochondria
In co-cultures of neurons and microglia, the team noted an increase in TNTs connecting the two when toxic proteins built up within neurons. These nanotubes were found to contain particles of alpha-synuclein and tau. The transfer of pathological proteins happened from neurons to microglia for degradation, rather than the other way around. This illustrates that microglia can effectively relieve neurons of toxic protein burdens and concurrently transport mitochondria to the affected cells through the same TNTs.
Mitochondria play a crucial role in maintaining cellular functions; when they malfunction, it can lead to energy shortages and oxidative stress. Alpha-synuclein and tau can disrupt mitochondrial function, contributing to neuronal damage and death in neurodegenerative diseases. When microglia provided healthy mitochondria to affected neurons, the researchers observed a restoration of energy production and a reduction in oxidative damage, effectively safeguarding neuronal function and survival.
Overall, these findings indicate that by removing protein aggregates from neurons and delivering functional mitochondria, microglial TNTs play a direct role in promoting neuronal health and potentially slowing the progression of neurodegeneration.
Investigating Genetic Mutations’ Effects
Subsequently, the researchers explored whether existing genetic mutations linked to neurodegenerative diseases influenced the formation and functionality of tunneling nanotubes and their protective mechanisms. They determined that mutations in the LRRK2 and Trem2 genes—associated with Parkinson’s and frontotemporal dementia respectively—either hindered aggregate removal or compromised the transfer of functional mitochondria. Additionally, mutations related to Parkinson’s in the Rac1 gene may also influence the creation and performance of TNTs.
These findings suggest new pathways through which known genetic mutations might contribute to neurodegenerative disorders. By hindering TNT-enabled neuroprotective processes, these genetic changes limit microglia’s ability to adequately support neurons. Targeting these genes could present opportunities to enhance TNT formation and activation of cargo transfer through these nanotubes, potentially alleviating the progression of specific neurodegenerative conditions.
A Collaborative Effort Yielding Hopeful Insights
This research involved collaboration among several key contributors, including Dr. Daniele Bano, Prof. Donato Di Monte, and Prof. Eike Latz from the German Center for Neurodegenerative Diseases, Dr. Ádám Dénes from the Institute of Experimental Medicine in Budapest, Dr. Ronald Melki from the François Jacob Institute of Biology in Paris, and Prof. Hans-Christian Pape from the University of Münster. Thanks to their combined efforts and the data generated, these results pave the way for a deeper understanding of the brain and related disorders.
“This study has not only enhanced our comprehension of intercellular communication through tunneling nanotubes,” concludes Prof. Michael Heneka. “It has challenged traditional views of microglia as primarily contributors to neuroinflammation, revealing a new neuroprotective function and providing insights into potential therapeutic strategies for neurodegenerative disorders related to alpha-synuclein and tau pathology.”
