Summary: New research clarifies how neurodegenerative diseases such as Alzheimer’s can spread through the brain by moving toxic protein aggregates from one neuron to another.
Source: VIB Flanders.
Synapses—the contact points where neurons communicate—play a central role in transmitting toxic protein aggregates, a process that helps explain how neurodegenerative diseases like Alzheimer’s propagate across brain regions. This conclusion comes from research led by Professor Patrik Verstreken (VIB-KU Leuven) in collaboration with Janssen Research & Development (Johnson & Johnson). If scientists can block the transfer of these toxic proteins between cells, it could slow the progression of neurodegenerative disease. The results of the study are published in Cell Reports.
Neurodegenerative conditions, including Alzheimer’s disease, are associated with the accumulation and spread of abnormally folded proteins. As the disease advances, pathological protein aggregates appear in more brain regions and compromise increasingly large neural networks.
Professor Patrik Verstreken (VIB-KU Leuven) explains: “You can picture it like a drop of ink in a glass of water: over time the toxic material disperses through existing neuronal connections. We knew the disease followed existing brain pathways, but it was unclear which cellular processes actively drive that spreading.”
Synaptic transmission and uptake
The research team found clear evidence that synapses are key sites for passing toxic proteins between neurons and identified the cellular mechanisms involved. Their experiments show that toxic species are taken up by the receiving neuron inside small membrane-bound compartments called endocytic vesicles. Once inside, these vesicles can become compromised and release their harmful contents into the cell, allowing aggregates to seed further pathology.
Professor Verstreken adds: “Our data also connect genetic risk to the spreading process. Several human genetic variants influence Alzheimer’s risk, and one commonly observed variant called BIN1 directly impacts how toxic proteins move across synapses. In effect, BIN1 can enhance synaptic transmission of these aggregates, which facilitates their spread.”
Therapeutic implications and next steps
These findings suggest promising directions for therapy. By revealing how toxic proteins travel between neurons, the study points to potential strategies to block that transfer or to reroute aggregates toward cellular degradation pathways such as lysosomal clearance. Interfering with the uptake or endosomal release of aggregates could reduce propagation and slow disease progression.
Dr. Dieder Moechars (Scientific Director at Janssen Research & Development) cautions: “Our experiments were carried out in vitro, so the next critical step is to validate these models in living systems that recapitulate Alzheimer’s disease. Now that we understand aspects of the spreading mechanism, we must devise targeted ways to disrupt it.”
Source: Sooike Stoops – VIB Flanders
Image Source: This NeuroscienceNews.com image is in the public domain.
Original Research: Full open-access research: “Loss of Bin1 Promotes the Propagation of Tau Pathology” by Sara Calafate, William Flavin, Patrik Verstreken, and Diederik Moechars in Cell Reports. Published online October 18, 2016. doi:10.1016/j.celrep.2016.09.063
Abstract
Loss of Bin1 Promotes the Propagation of Tau Pathology
Highlights
- Endocytosis influences the propagation of Tau pathology in neuronal culture models.
- BIN1 acts as a negative regulator of endocytic flux.
- Lower BIN1 levels correlate with increased propagation of Tau pathology.
- Internalized Tau aggregates compromise endosomal membranes.
Summary
Tau pathology spreads within synaptically connected neuronal circuits, but the cellular mechanisms that enable this propagation have been unclear. BIN1 (also known as amphiphysin 2) is the second most prevalent genetic risk factor for late-onset Alzheimer’s disease, and in affected human brains the neuronal isoform of BIN1 is downregulated. The study demonstrates that reducing neuronal BIN1 levels enhances Tau pathology propagation while overexpressing neuronal BIN1 reduces propagation, in two independent in vitro models. Increased spread of Tau aggregates is driven by elevated endocytosis, consistent with the finding that BIN1 limits endocytic flux. Pharmacological inhibition of endocytosis also reduces Tau propagation. Using a galectin-3 binding assay, the authors show that internalized Tau aggregates can damage endosomal membranes, allowing aggregates to escape into the cytoplasm where they propagate pathology. Overall, lower BIN1 levels facilitate Tau spread by promoting the internalization and endosomal trafficking of aggregates.
“Loss of Bin1 Promotes the Propagation of Tau Pathology” by Sara Calafate, William Flavin, Patrik Verstreken, and Diederik Moechars in Cell Reports. Published online October 18, 2016. doi:10.1016/j.celrep.2016.09.063