A hallmark of Alzheimer's and other dementias is the spreading and build-up of misfolded tau protein inside brain cells. Toxic tau proteins have been found within tiny lipid-enclosed structures called extracellular vesicles that actively ferry materials between cells. Vesicles containing tau might actually be spreading the bad protein to healthy cells, worsening the disease. It had been proposed that vesicles might be a way for brain cells to dispose of unwanted tau, but this had never been directly visualised.
The research team used deep proteomic profiling (Dr Darragh O'Brien and Prof Roman Fischer, Oxford Target Discovery Institute) to analyse the contents of extracellular vesicles from the brains of people diagnosed with Alzheimer's Disease. They discovered that secreted vesicles originating from the cell's waste disposal system contained toxic filamentous versions of tau proteins thought to be particularly damaging and difficult for cells to clear.
Using cryogenic electron microscopy, Dr Ryskeldi-Falcon and Tiana Behr determined that the structure of tau filaments within vesicles was similar, but not identical to the previously-reported tau structure in Alzheimer's Disease. The team discovered that tau in extracellular vesicles is in complex with an extra density that runs along the length of the filament, potentially offering clues into partner molecules that may encourage their toxic assembly.
Imaging of whole, intact extracellular vesicles indicated that the tau cargoes were attached, or tethered to the inner vesicle walls, hinting at a specific mechanism for tau packaging into vesicles.
This research provides critical insights into the formation and spread of toxic tau, paving the way for new therapies aimed at blocking tau transmission and potentially slowing or halting Alzheimer's progression. The identification of tau-carrying vesicles also offers a potential pathway for earlier diagnosis. Targeting the attachment of tau to these vesicles represents a promising strategy to disrupt the spread of harmful tau filaments.
Dr Steph Fowler's current research programme at the Oxford-GSK IMCM uses neuronal models of tauopathy to track toxic tau forms from their genesis to their secretion. Using multiomic tools and super-resolution microscopy, her team aims to uncover novel therapeutic targets to prevent or slow the spread of tauopathy.
Read the full article in Nature Neuroscience: https://www.nature.com/articles/s41593-024-01801-5