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.
Highlights
Neurodegenerative tauopathies including Alzheimer’s disease (AD) are tightly associated with the intracellular accumulation of aberrantly aggregated tau protein within the brain [20, 24]
We demonstrated that brain slice culture (BSC) transduced with microtubule-associated protein tau (MAPT) encoding the P301L/S320F double mutation [10, 50] develop an abundance of mature neurofibrillary pathology by 28 days in vitro (DIV)
Using long-term optical pulse labeling studies in BSCs we find that pro-aggregant P301L/S320F-tau-Dendra2 forms neuronal tau inclusions rapidly (12–96 h) and that these inclusions once formed show appreciable daily turnover with an overall half-life of ~ 7 days
Summary
Neurodegenerative tauopathies including Alzheimer’s disease (AD) are tightly associated with the intracellular accumulation of aberrantly aggregated tau protein within the brain [20, 24]. Unbound microtubule-associated protein tau (MAPT) exists physiologically as a soluble unstructured protein, but under pathogenic conditions tau assembles into insoluble β sheet-rich amyloidogenic fibrillar inclusions in AD and other tauopathies [20, 24, 31]. These inclusions are extensively post-translationally modified, with prominent hyperphosphorylation. Prion-like mechanisms of seeding and propagation of tau inclusions are wellestablished in many model systems, and are proposed as mechanisms for the spread of tau pathology [23]. BSCs are highly predictive of results obtained upon transgenic or rAAVmediated expression of tau in rodent models [35]
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