Investigating the mechanisms of tau secretion across neuronal networks in health and disease.

Abstract

The accumulation of insoluble neurofibrillary tangles, composed of hyperphosphorylated tau, is one of the main pathological hallmarks of tauopathies. Growing evidence indicates that the release and re-uptake of pathogenic tau seeds mediates the spread of tau pathology along living and intact neuronal networks via ‘prion-like’ mechanisms. Moreover, there is evidence showing that neuronal activity can regulate tau secretion and accelerate cell-to-cell propagation of tau pathology in vitro and in vivo. What molecular mechanisms drive and mediate activity-dependent secretion of physiological and pathological tau remains to be investigated. Sensitive biosensors that are able to monitor the release and re-uptake of tau in connected neuronal networks under different conditions are currently limited. Split nanoluciferase (NLuc) complementation reporters, which are composed of two subunits, a large bit (LgBiT; 17.6kDa) and a smaller bit (HiBiT; 11 amino acid) is a highly-sensitive bioluminescent biosensor that can be used to monitor cell-to-cell transfer of tau in different conditions. Structural complementation of the split HiBiT and LgBiT reporters re-constitutes the NLuc enzyme, which generates a bright luminescent signal. Tagging tau with these reporters will allow the mechanisms of tau release and re-uptake to be closely dissected, under pathological and physiological conditions. A greater understanding of the mechanism involved in the spread of tau pathology will help in the development of effective treatments in the future.

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Identifiers

ORCID for Dianne Marquez Lopez: orcid.org/0009-0004-6395-452X

ORCID for Katrin Deinhardt: orcid.org/0000-0002-6473-5298

ORCID for Jonathan West: orcid.org/0000-0002-5709-6790

ORCID for Mark Coldwell: orcid.org/0000-0002-6243-3886

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