Chandelier
Senior Member (Voting Rights)
Editor’s summary
Synaptic connections mediate classical intercellular communication in the brain. However, recent data have demonstrated the existence of noncanonical routes of interneuronal communication mediating the transport of materials including calcium, mitochondria, and pathogenic proteins such as amyloid beta (Aβ). Using super-resolution and electron microscopy, Chang et al. identified and characterized structures called nanotubular bridges that connect dendrites in the brain (see the Perspective by Budinger and Heneka). These bridges mediate the transport of calcium ions, small molecules, and Aβ peptides, and may contribute to the spreading and accumulation of pathological Aβ in Alzheimer’s disease. —Mattia MarosoStructured Abstract
INTRODUCTION
Communication between neurons is fundamental to brain function and has long been thought to occur primarily through specialized junctions called synapses. However, the observed transfer of large molecules and proteins between neurons suggests the existence of other, less understood communication pathways. In other biological systems, long-range intercellular transport is mediated by ultrathin membrane bridges known as nanotubes. These structures can transport a vast range of materials, from small ions (10−10 m) to large mitochondria (10−6 m). Despite their potential importance, the fragile, dynamic nature of nanotubes and a lack of specific markers have made them difficult to study in tissue, leaving their existence and physiological role in the brain unconfirmed. We hypothesized that a network of these nanotubes forms an additional layer of neuronal connectivity, operating in parallel with synapses.RATIONALE
In other cell types, nanotubes often form when thin, exploratory cell protrusions contact a neighboring cell and establish a stable connection. In the brain, dendritic protrusions, known as filopodia, have historically been viewed only as precursors to synapses. The possibility that they could form nonsynaptic connections with other dendrites has been largely overlooked. Our investigation began by reexamining existing high-resolution electron microscopy images of mouse and human brain tissue. We discovered instances where a filopodium from one neuron’s dendrite formed a direct, membrane-to-membrane contact with the dendrite of a neighboring neuron without any of the typical structural features of a chemical synapse. This observation led us to propose that these were a previously unidentified form of neuronal connection: dendritic nanotubes.RESULTS
By using advanced superresolution microscopy on specially prepared mouse brain tissue, we visualized these dendritic nanotubes connecting pyramidal neurons in the primary visual cortex. A machine learning–based classification confirmed that their shape was distinct from that of synaptic structures. In cultured neurons, we observed these nanotubes forming dynamically and confirmed that they possessed a distinct internal structure, setting them apart from other neuronal extensions. Functionally, these neuronal nanotubes created a path for calcium signals to travel between connected neurons; blocking nanotube formation halted this nonsynaptic transfer.To test whether these nanotubular structures could transport disease-related molecules, we injected human β-amyloid (Aβ), a peptide central to Alzheimer’s disease (AD), into a single neuron in a mouse brain slice. The peptides spread to neighboring neurons, and this propagation was stopped when nanotube formation was inhibited, confirming that the nanotubes acted as direct conduits.
Lastly, we investigated the role of these dendritic nanotubes in a mouse model of AD. We found that the nanotube network was significantly altered early in the disease, even before the formation of amyloid plaques, a hallmark of AD. Our computational model supported these findings, predicting that overactivation in the nanotube network could accelerate the toxic accumulation of amyloid in specific neurons, thereby providing a mechanistic link between nanotube alterations and the progression of AD pathology.
CONCLUSION
This study provides the first comprehensive characterization of a nanotubular communication network in the brain, establishing a new framework for nonsynaptic signaling between neurons. By demonstrating that these dendritic nanotubes can transport disease-implicated proteins, such as Aβ, we have revealed a previously unknown mechanism that may contribute to the spread of pathology in the early stages of neurodegenerative disorders. The discovery of this parallel neural network opens up entirely new avenues for research into brain connectivity, intercellular communication, and the fundamental processes driving neurological disease.
Neuronal nanotubes mediate intercellular transport and disease.
We identified dendritic nanotubes (DNTs) as a nonsynaptic communication network in the brain. (A) These structures form direct conduits between neurons, transporting substances such as calcium and Aβ. (B) In a mouse model of AD, alterations in this network are associated in pathological Aβ accumulation, suggesting a previously unidentified mechanism for the spread of neurodegenerative pathology.