The accumulation of pathological proteins in neurodegenerative disorders such as Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease is a major characteristic of these conditions. These proteins, such as alpha-synuclein and tau, can aggregate abnormally inside neurons, disrupting cellular function. Recent research has shown that microglia, specialized immune cells in the brain, can form tunnelling nanotubes (TNTs) to connect with neurons and transfer cargo, such as toxic protein accumulations, to alleviate neuronal damage. This transfer of material between neurons and microglia via TNTs plays a crucial role in maintaining cellular health and supporting neurons in times of need.
Using live cell imaging microscopy, researchers have observed the formation of connections between neurons and microglia through TNTs. In co-cultures of neurons and microglia, it was found that microglia can rescue neurons from toxic protein accumulations by transferring the proteins to be degraded and transferring healthy mitochondria to restore vital functions. This process significantly reduces oxidative stress, restores energy production, and ultimately promotes the survival and functioning of neurons in neurodegenerative diseases.
Mitochondria are crucial components of cells, and when they function improperly, it can lead to energy deficits and oxidative stress. The transfer of healthy mitochondria from microglia to affected neurons helps to restore energy production, reduce oxidative damage, and preserve neuronal functioning. By clearing protein aggregates from neurons and transferring functional mitochondria through TNTs, microglia directly support neuronal health and can help to slow down the progression of neurodegeneration in various disorders.
Research has shown that genetic mutations associated with neurodegenerative diseases can impact the formation of TNTs and the rescue mechanisms mediated by these nanotubes. Mutations on genes such as LRRK2, Trem2, and Rac1, linked to Parkinson’s disease and frontotemporal dementia, can affect the removal of protein aggregates and the delivery of functional mitochondria. Understanding how genetic mutations influence TNT formation and functionality can provide insights into potential therapeutic strategies for neurodegenerative conditions linked to alpha-synuclein and tau pathology.
An international collaboration involving key researchers from various institutions has been instrumental in conducting this research and generating promising results. The study has deepened our understanding of intercellular communication through TNTs, challenged conventional views of microglia’s role in neuroinflammation, highlighted a novel neuroprotective mechanism, and offered insights into potential therapeutic strategies for neurodegenerative diseases. By targeting genetic mutations that disrupt TNT-mediated neuroprotective mechanisms, researchers may be able to enhance TNT formation and transfer via these nanotubes to help mitigate neurodegenerative disease progression.