Study explores association between Tau filaments and extracellular vesicles in Alzheimer’s disease

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder associated with a progressive decline in memory and mental abilities, which can significantly hinder people’s ability to complete daily tasks. Past studies found that patients diagnosed with AD, as well as some other neurodegenerative disorders, exhibit an abnormal accumulation of tau protein in their neurons.

Tau protein is a microtubule-associated protein (MAP) known to stabilize the internal structure of neurons, binding to microtubules. These are microscopic tubular structures that support the transport of nutrients, proteins and other vital molecules within individual neurons or other cells.

Recent findings suggest that tau proteins interact with extracellular vesicles (EVs), small membrane-bound particles secreted by cells that carry molecules and deliver them to other cells. While the research hints at a connection between these vesicles and tau proteins in AD, the link between the two is not yet fully understood.

Researchers at the UK Dementia Research Institute at University College London, the Medical Research Council Laboratory of Molecular Biology and other institutes recently carried out a study aimed at further exploring the documented association between tau proteins and EVs using advanced experimental methods. Their findings, published in Nature Neuroscience, suggest that tau filaments are selectively packaged and tethered to EV membranes by specialized molecules.

“The abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including AD,” wrote Stephanie L. Fowler, Tiana S. Behr and their colleagues in their paper. “Assembled tau associates with EVs in the central nervous system of individuals with AD, which is linked to its clearance and prion-like propagation. However, the identities of the assembled tau species and EVs, as well as how they associate, are not known.”

The researchers examined EVs derived from the brains of deceased individuals with AD, using a combination of advanced experimental techniques. These techniques included quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy.

“We found tau filaments composed mainly of truncated tau that were enclosed within EVs enriched in endo-lysosomal proteins,” wrote Fowler, Behr and their colleagues. “We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging.”

The results gathered by this team of researchers offer new valuable insight about the intricate relationship between tau filaments and EVs in AD and potentially also some other neurodegenerative disorders. Most notably, Fowler, Behr and their colleagues found that tau filaments are tethered within EVs via molecules.

This key observation could be the focus of future research efforts, potentially leading to important new discoveries about the link between tau protein and EVs. In the future, these works could contribute to the development of alternative therapeutic strategies aimed at slowing down the progression of AD and other neurodegenerative diseases, potentially by targeting tau protein that is tethered to EVs.

“Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD,” wrote the researchers.

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