Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions

Abstract

Accumulation of the tau protein in fibrillar intracellular aggregates is a defining feature of multiple neurodegenerative diseases collectively referred to as tauopathies. Despite intensive study of tau, there is limited information on the formation and clearance dynamics of tau inclusions. Using rAAV vectors to mediate expression of Dendra2-tagged human wild-type, P301L and pro-aggregant P301L/S320F tau proteins, with and without the addition of exogenous tau fibrillar seeds, we evaluated tau inclusion dynamics in organotypic brain slice culture (BSC) models using long-term optical pulse labeling methodology. Our studies reveal that tau inclusions typically form in 12–96 h in tauopathy BSC models. Unexpectedly, we demonstrate appreciable turnover of tau within inclusions with an average half-life of ~ 1 week when inclusions are newly formed. When BSCs with inclusions are aged in culture for extended periods, tau inclusions continue to turnover, but their half-lives increase to ~ 2 weeks and ~ 3 weeks after 1 and 2 months in culture, respectively. Individual tau inclusions can be long-lived structures that can persist for months in these BSC models and for even longer in the human brain. However, our data indicate that tau inclusions, are not ‘tombstones’, but dynamic structures with appreciable turnover. Understanding the cellular processes mediating this inclusion turnover may lead to new therapeutic strategies that could reverse pathological tau inclusion formation.

Tau isoforms are differentially expressed across the hippocampus in chronic traumatic encephalopathy and Alzheimer’s disease

“…It has become evident that 3R and 4R tau do not exist in a static state and can change over the course of disease. Recent work has suggested that although the tau inclusions are long lived, they are dynamic structures with consistent turnover of smaller parts [ 10 ]. Through still unclear mechanisms, the current results suggest that 3R tau becomes preferentially added into the tau fibril as disease severity increases.…”

Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

“…Tau pathology upon patient tau injection in WT animals also developed relatively slowly and, interestingly, was decreased at 9 months after injection [ 110 ]. This latter finding could be potentially explained by intracellular tau fibril degradation, as described in a recent study using an organotypic brain slice model [ 119 ].…”

Spontaneous Isomerization of Asp387 in Tau is Diagnostic for Alzheimer’s Disease: An Endogenous Indicator of Reduced Autophagic Flux

“…44 It may be difficult to accommodate succinimide formation in such close proximity to densely packed fibrils where the structural flexibility required for isomerization to occur is likely to be hindered. Finally, recent results have demonstrated that tau exchanges dynamically in and out of NFTs, 45 which further complicates the relationship between tau and NFT lifetimes. Similar arguments apply to the possibility that degree of isomerization might represent overall NFT abundance.…”