A clearance mechanism involving microglia has been known to relieve neurons of toxic protein aggregates such as those associated with Alzheimer’s disease and Parkinson’s disease. Unfortunately, this mechanism hasn’t been understood very well, certainly not well enough to suggest any new treatment strategies. But now a new study has revealed what may be the mechanism’s central feature: the formation of tunneling nanotubes (TNTs).
The study was led by Michael T. Heneka, MD, director of the Luxembourg Center for Systems Biomedicine (LCSB) at the University of Luxembourg. Heneka and his LCSB colleagues, as well as colleagues from the University Hospital Bonn, the German Center for Neurodegenerative Diseases, and other institutions, presented their findings in the journal Neuron, in an article titled, “Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes.”
The scientists used live cell imaging to observe TNTs between neurons and microglia in cell cultures derived from either mouse models or human stem cells. The TNTs, which formed in both physiological and pathological conditions, facilitated the rapid exchange of organelles, vesicles, and protein aggregates—specifically, toxic aggregates of alpha-synuclein and tau, which accumulate within neurons in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases.
“Our research demonstrates that microglia use TNTs to extract neurons from these aggregates, restoring neuronal health,” the article’s authors wrote. “Additionally, microglia share their healthy mitochondria with burdened neurons, reducing oxidative stress and normalizing gene expression.”
When mitochondria don’t function properly, energy deficits and oxidative stress can result. Both alpha-synuclein and tau can impair mitochondrial activity, contributing to the dysfunction and death of neurons in neurodegenerative diseases. Remarkably, when microglia transferred healthy mitochondria to affected neurons, the scientists noticed that it restored energy production and reduced oxidative damage, effectively preserving neuronal functioning and survival.
“Further research is needed to understand the formation and function of TNTs in detail, but it was thrilling to observe that microglia play an active role in maintaining neuronal health and supporting neurons in times of need,” said Hannah Scheiblich, PhD, first author of the article who worked with Heneka at the University Hospital Bonn and the German Center for Neurodegenerative Diseases.
The researchers also investigated whether known genetic mutations associated with neurodegenerative diseases influenced the formation of tunnelling nanotubes and the TNT-based rescue mechanisms. They observed that mutations on the LRRK2 and Trem2 genes, respectively linked to Parkinson’s disease and frontotemporal dementia, either reduced aggregate removal or compromised the delivery of functional mitochondria. Additionally, alterations linked to Parkinson’s in gene Rac1 could also affect TNT formation and functionality.
These results indicate new ways by which known genetic mutations may be contributing to neurodegenerative diseases. By disrupting TNT-mediated neuroprotective mechanisms, these genetic variants prevent microglia from supporting neurons effectively. Targeting these genes may provide an avenue to enhance TNT formation and activate transfer via these nanotubes, which may in turn help mitigate the progression of certain neurodegenerative diseases.
“This study has not only deepened our understanding of intercellular communication through tunnelling nanotubes,” Heneka concluded. “It has challenged the conventional view of microglia as contributors to neuroinflammation, highlighted a novel neuroprotective mechanism, and offered insights into potential therapeutic strategies for neurodegenerative conditions linked to alpha-synuclein and tau pathology.”
