Time-resolved fluorescence data suggest Tau aggregation propagate to healthy neurons in a prion-like way

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Mathis L.  
By Mathis L.    time to read 2 min

Tau aggregation in neurons

Alzheimer’s disease pathogenesis and tau aggregation propagation
Postulated model for Alzheimer’s disease pathogenesis and tau aggregation propagation

Alzheimer’s disease is largely known as one of the most prevalent neurodegenerative diseases worldwide. While the exact pathogenesis of this disorder is yet to be described, Tau protein has been widely viewed as a key player in that process. In particular, the aggregation of Tau protein in neurons has repeatedly correlated to Alzheimer’s disease progress in patients.

Recent findings have introduced the notion of a “disease seeding” process in which Tau aggregates, called seeds, travel between neurons and trigger pathological behavior and neurodegeneration in healthy cells. This spreading mechanism could be the main driver of the disease progress and a revolutionary therapeutic approach if properly understood and addressed.

One of the latest publications looking into this topic is the work of the French team Courade et al (2018). They described an HTRF-based Tau aggregation assay format to monitor the induction of Tau aggregation in healthy cells in a seeding situation and designed an experiment to assess the feasibility of the process.

Assay principle

Tau aggregation assay principle
Anti-tau antibodies are coupled with either an HTRF donor or acceptor. They bind to tau protein on a single epitope which ensures single-antibody binding per protein. In case of tau aggregation, HTRF donor and acceptor are brought in proximity which triggers FRET.

Tau seeding experiment

Tau-seeding assay principle
Healthy cells expressing or lacking Tau are incubated with tau aggregates (tau seeds) and tau aggregation is measured for each population. tau seeding triggered tau aggregation in tau expressing cells. The absence of aggregates in cells lacking tau demonstrates the elimination of initial seeds overtime.

Interestingly, their observations indeed concluded on the ability of Alzheimer’s disease Tau aggregates to enter healthy neurons and initiate pathological Tau aggregation within them.

While these findings add evidence for an even more complex pathogenesis of this neurodegenerative disorder than though a few years ago, Courade’s team did not stop here and took their assay a step further to screen Tau antibodies. Results from those screens allowed for a better understanding of the antibody characteristics that allow for a more potent Tau seeding inhibition, namely affinity and phosphorylation-specificity. They also drew attention to the existence of varying epitopes between Tau aggregates which could be challenging for antibody-based seeding inhibition therapies.

Application note - Monitor Tau Aggregation

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