Introduction
Key definitions
Name | Definition | Structural criteria | Molecular criteria |
---|---|---|---|
Tau pathology | Broad term designing abnormal molecular changes of normal tau as well as morphological changes. | Mislocalization of tau and/or pathological tau assembly in inclusion or aggregate. | Post-translational modifications of tau. Tau insolubility. |
Tau inclusion | Morphologically distinct subcellular structure inside a cell. | Microscopically visible structure. Made of tau aggregates. | Properties of tau aggregates. |
Tau aggregate | Assembly of tau into oligomers, fibrils, filaments, and NFT | Molecular tau assembly based on highly ordered ß-sheet structure. | Positive with ß-sheet (amyloid) sensitive dyes (Thioflavine T, Congo Red, LCOs). Tau hyperphosphorylation |
Tau seed | A tau species inducing aggregation of tau | Molecular tau assemblies of various size providing a template | Positive with ß-sheet sensitive dyes |
Liquid coacervates of tau | Membraneless organelles in a state of Liquid-liquid phase separation | Coacervation of tau into liquid droplets | Can acquire ß-sheet structure. |
Tangles | Neuronal tau inclusions in somata | Composed of bundles of PHFs and SFs. Gallyas and Campbell-Switzer positive. | 3R and 4R tau positive in AD |
Neuropil threads | Tau inclusions in nerve cell dendrites | Composed of bundles of PHFs and SFs. Gallyas and Campbell-Switzer positive. | 3R and 4R tau positive in AD |
Dystrophic neurites | Axons forming the neuritic corona of plaques | Nerve cell processes in contact with Aß deposits. Some of them contain PHFs and SFs and are Gallyas and Campbell-Switzer positive. | 3R and 4R tau positive in AD |
Argyrophilic grains | Neuronal granular tau inclusions in dendrites | Tau filaments. Gallyas positive. Campbell-Switzer negative. | 4R tau positive in AGD |
Pick bodies | Spherical tau inclusions in nerve cell somata | Filamentous and vesicular material. Gallyas-negative. Campbell-Switzer positive. | 3R tau positive in Pick disease. |
Oligodendroglial coiled bodies | Tau inclusions in cell bodies of oligodendrocytes | PHF/SF like filaments. Gallyas positive. Campbell-Switzer negative. | 4R tau positive in PSP and CBD |
Globular oligodendroglial inclusions | Globular oligodendroglial tau inclusion | Gallyas positive. | Mainly 4R tau positive in GGTs |
Tufted astrocytes | Astrocytes with thin and long radial processes containing tau inclusions | Tau filaments in cytoplasm and proximal portions of astrocytic processes. Gallyas positive. Campbell-Switzer negative. | 4R tau positive in PSP |
Astrocytic plaques | Astrocytes containing tau inclusions in a corona-like arrangment | Tau filaments in distal portions of astrocytic processes. Gallyas positive. Campbell-Switzer negative. | 4R tau positive in CBD |
Thorn-shaped astrocytes | Astrocytes with thorn-shaped processes containing tau inclusions | Spine-like perinuclear tau filaments. Gallyas positive. | 4R tau positive in ARTAG |
Round table discussion and questions for tau research
Tau aggregation
Mechanisms of tau aggregation
Assembly of different tau isoforms
Role of tau phosphorylation and other posttranslational changes in aggregation
Recommendations and cautionary notes:
Impact of tau mutations and tau levels on tau aggregation
Role of other neurodegenerative-related proteins in tau aggregation
What is the evidence for prion-like propagation of tau aggregates?
Evidence for tau-induced seeding: cellular uptake and induction of aggregation
Tau species | Derived from | seeding assay | Noteworthy features | Ref |
---|---|---|---|---|
P301S tau tg brain derived sarkosyl insoluble tau Recombinant P301S aggregates | P301S tau transgenic mouse brain (at symptomatic stages of disease) Heparin induced in vitro aggregation | Cell based P301S tau aggregation assay wherein insoluble tau inclusions formed within cells and were visualised by light microscopy and verified using biochemical insolubility assays. Sarkosyl insoluble P301S tau aggregates enriched in 30-50% sucrose fractions were verified by EM | 1. Sarkosyl insoluble P301S tau from mouse brain has greater seeding capacity than total brain homogenate from P301S transgenic mice. | [45] |
2. Native (sarkosyl insoluble) P301S tau from mouse brain has greater seeding competence than recombinant P301S tau aggregates | [45] | |||
3. In vitro phosphorylation of recombinant P301S tau seeds does not increase their seeding competence. | [45] | |||
4. Seeding capacity of recombinant P301S tau becames equivalent to that of sarkosyl insoluble P301S tau from tg mouse brain when incubated with it in vitro. | [45] | |||
5. Sarkosyl insouble P301S tau from tg mouse brain separates into 30-50% sucrose fractions and comprises of AT8 and AT100 positive 6-10mer tau oligomers and short tau fibrils | [79] | |||
AD brain derived sarkosyl soluble and insoluble tau | Fresh frozen AD brain homogenate (Braak stages 1-3) | FRET based cellular aggregation of CYP/RFP-tagged P301S-RD tau | 1. In a significant number of cases, there was no biochemically evident insoluble tau (Braak stages 1-3) but the brain homogenates displayed strong seeding ability. | [48] |
Recombinant P301S-RD tau oligomers and short fibrils | Heparin induced in vitro aggregation | Split luciferase based cellular aggregation of NLuc and Cluc-tagged P301S-RD tau | 1. Tau trimers were smallest seed competent tau oligomers | [93] |
AD brain derived tau oligomers | Fresh frozen AD brain | Split luciferase based cellular aggregation of NLuc and Cluc-tagged P301S-RD tau | 1. Though tau oligomers extracted from AD brain ranging in size from n = 1 to n > 20, only oligomers equal to or greater than n = 3 exhibited seeding ability. | [93] |
P301S tau tg brain derived undefined pathological tau species | P301S tau tg mouse brain homogenates (at pre-symptomatic and symptomatic stages) | FRET based cellular aggregation of CYP/RFP-tagged P301S-RD tau | 1. Seeding activity detected as early as 1 month of age prior to emergence of misfolding (MC1 immunoreactivity which emerged at 3 m) or hyperphosphorylation (AT8 immunoreactivity which emerged at 6 m) | [71] |
Recombinant RD-tau “strains” of distinct morphologies | Exposure of stably transfected cells expressing YFP-tagged P301L/V337M-RD tau to recombinant tau fibrils led to emergence of morphologically distinct tau inclusions; colonies of cells with the same inclusion were amplified and the relevant tau inclusion was stably propagated in a clonal fashion | Induction of morphologically distinct fluorescent accumulates of RD-tau evident by light microscopy following exposure to tau seed | 1. Morphologically distinct tau strains were evident with different aggregation propensities and seeding abilities 2. Tau strains propagated morphologically distinct inclusions stably in cell culture and in vivo through successive generations | [112] |
Recombinant 2N4R tau seeds Sarkosyl insoluble AD brain tau | Repetitive self seeded fibrilisation of recombinant 2N4R tau in vitro led to progressive increase in insoluble tau fibrils verified by EM AD-tau seed induced fibrillisation of recombinant 2N4R tau in vitro verified by EM | Induction of tau inclusions in rodent neurones NOT expressing exogenous human tau following exposure to tau seed Induction of tau inclusions in rodent neurones NOT expressing exogenous human tau following exposure to tau seed | 1. Seeds derived from human AD brain (and therefore comprising of wild-type human tau) capable of inducing aggregation of wild-type rodent tau at physiological expression levels. 2. Induction of aggregation in cells verified by biochemical insolubility assays 3. Sarkosyl insoluble AD tau more seed competent than recombinant tau seeds generated in vitro but former able to confer its higher seeding competence to latter if seeded with it. | [65] |
Evidence for prion-like spread: Propagation of tau aggregates and their release
Physiological tau secretion
Recommendation
Transcellular tau transfer
Neuroanatomical spreading of tau aggregates
Cautionary notes and recommendations
Evidence for trans-synaptic and non-synaptic transmission of tau pathology
The nature of the tau species that spread/ propagate
What is the evidence for “tau strains or conformers”?
What is the evidence that propagation of tau aggregates is toxic?
Dissociation between aggregation, propagation and toxicity
Different pathological tau species employ different mechanisms of toxicity
Pathological change and Tau species implicated | Potential modes of tau toxicity | Selected References |
---|---|---|
Hyperphosphorylation (e.g. soluble monomer/dimer) | Loss Of microtubule-binding (and other) Function(s) (LOF) leading to axonal transport and synaptic defects reflected in mitochondrial clumping, Golgi disruptions and mis-sorting of synaptic proteins. Mis-localisation may also be evident causing Gain Of toxic Function (GOF). Collectively these may be responsible for neuronal dysfunction at early stages of disease. It is possible that a partial LOF is required for, and leads to an eventual GOF | |
Misfolding/aberrant folding and aggregation into small aggregates (e.g. sarkosyl soluble oligomers) | Neuronal dysfunction and neurodegeneration evident in some models in the absence of larger aggregates implying that smaller soluble oligomeric species responsable for these phenotypes | |
Aggregation (into large insoluble oligomers such as granular tau oligomers and filaments including tangles) | Space-occupying lesions resulting in GOF. Toxicity debated because in some models rescue of neuronal dysfunction and degeneration evident despite persistence of larger aggregates. |