Pathological protein accumulation is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease, frontotemporal dementia and Parkinson’s disease. Proteins such as alpha-synuclein and tau can abnormally accumulate inside neurons, thereby disrupting essential cellular function. “We knew that microglia play a role in clearing these protein aggregates, but we recently learned that they can form tunneling nanotubes – long extensions that can connect distant cells in the brain,” explains Professor Michael Heneka, Director of the LCSB, head of the Neuroinflammation group and senior author of the paper. “With this study, we wanted to better understand the charge transfer between neurons and microglia via these nanotubes and explore the consequences of this exchange for cellular health.”
The researchers employed cultures of neurons and microglia, derived from mouse models or human stem cells, and used cutting-edge imaging technology to show that microglia make contact with neurons via tunneling nanotubes (TNTs) to relieve them of toxic protein buildup. Furthermore, microglia transfer healthy mitochondria, the cells’ energy powerhouses, to affected neurons, significantly reducing oxidative stress, restoring vital functions, and ultimately rescuing these nerve cells.
Live imaging of tunneled nanotubes
Using live cell imaging microscopy, the scientists observed the formation of connections between neurons and microglia.
“Further research is needed to understand the formation and function of TNTs in detail, but it was exciting to observe that microglia play an active role in maintaining neuronal health and supporting neurons in times of need,” explains Dr. Hannah Scheiblich, first author of the paper who worked with Prof. Heneka at the University Hospital Bonn and the German Center for Neurodegenerative Diseases.
Microglia rescue neurons by removing proteins and donating mitochondria
In co-cultures of neurons and microglia, the team further observed that when toxic proteins accumulate in neurons, the amount of TNTs connecting the two cell types increases, and that these nanotubes contain alpha-synuclein and tau particles. Pathological proteins are transferred from neurons to microglia, not the other way around, where they are degraded over time. The results not only demonstrated that microglia can effectively relieve neurons of toxic protein loads, but also transfer mitochondria to affected neurons via the same TNTs.
Mitochondria are important components of cells, and when they do not function properly, they can lead to energy deficits and oxidative stress. Both alpha-synuclein and tau can impair mitochondrial activity, contributing to neuron dysfunction and death in neurodegenerative diseases. Surprisingly, when microglia transferred healthy mitochondria to affected neurons, scientists noticed that this restored energy production and reduced oxidative damage, effectively preserving neuronal function and survival.
Taken together, these findings suggest that by removing protein aggregates from neurons and transferring functional mitochondria, microglial TNTs directly support neuronal health and may mitigate the progression of neurodegeneration.
Exploring the impact of genetic mutations
The researchers then investigated whether known genetic mutations associated with neurodegenerative diseases influenced TNT formation and rescue mechanisms. They found that mutations in the genes LRRK2 and Trem2, linked respectively to Parkinson’s disease and frontotemporal dementia, reduced aggregate clearance or compromised the delivery of functional mitochondria. Furthermore, Parkinson’s-linked alterations in the Rac1 gene could also affect TNT formation and functionality.
These results indicate new ways in which known genetic mutations may contribute to neurodegenerative diseases. By disrupting TNT-mediated neuroprotective mechanisms, these genetic variants prevent microglia from effectively supporting neurons. Targeting these genes may provide a pathway to enhance TNT formation and activate transfer across these nanotubes, which in turn may help mitigate the progression of certain neurodegenerative diseases.
An international collaboration to obtain promising results
This research work was carried out with several key collaborators, 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 this team effort and the jointly generated dataset, the results open promising avenues with regard to understanding the brain and its associated diseases.
“This study has not only deepened our understanding of intercellular communication via tunneling nanotubes,” concludes Professor Michael Heneka. “It has challenged the conventional view of microglia as contributors to neuroinflammation, highlighted a novel neuroprotective mechanism, and provided insights into potential therapeutic strategies for neurodegenerative diseases linked to alpha-synuclein and tau pathology.”