Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice

Guo, Jing; Narasimhan, Sneha; Changolkar, Lakshmi; He, Zhuohao; Stieber, Anna; Zhang, Bin; Gathagan, Ronald J.; Iba, Michiyo; McBride, Jennifer D.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1084/jem.20160833

Cited by 345 publications

(568 citation statements)

References 61 publications

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Section: Discussionmentioning

confidence: 99%

“…However, it is likely that tau aggregates within brain lysate have higher seeding potencies than recombinant tau fibrils (54). Indeed the cerebral injection of human tauopathy brain lysates can induce local tau pathology, or pathology that spreads along connected brain regions, in non-transgenic mice (33,66).We showed that aggregated P301L tau failed to sequester soluble WT tau into insoluble aggregates when co-expressed in the HEK293T seeding model, demonstrating that even when intracellular tau aggregates are generated, WT tau is resilient to recruitment into inclusions. Given that there seemed to be less aggregation of P301L tau in the presence of WT tau expression, it is plausible that WT tau may reduce templated conformation of P301L tau.…”

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confidence: 83%

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Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Strang¹,

Croft²,

Sorrentino³

et al. 2018

Journal of Biological Chemistry

104

139

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The accumulation of aberrantly aggregated microtubule-associated protein tau (MAPT) 1 defines a spectrum of tauopathies, including Alzheimer's disease. Mutations in the MAPT gene cause frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), characterized by neuronal pathological tau inclusions in the form of neurofibrillary tangles and Pick bodies, and in some cases glial tau pathology. Increasing evidence points to the importance of prion-like seeding as a mechanism for the pathological spread in tauopathy and other neurodegenerative diseases. Herein, using a cell culture model, we examined a multitude of genetic FTDP-17 tau variants for their ability to be seeded by exogenous tau fibrils. Our findings revealed stark differences between FTDP-17 tau variants in their ability to be seeded, with variants at proline 301 and serine 320 showing robust aggregation with seeding. Similarly, we elucidated the importance of certain tau protein regions and unique residues, including the role of proline 301 in inhibiting tau aggregation. We also revealed potential barriers in cross-seeding between 3-repeat and 4-repeat tau isoforms. Overall, these differences alluded to potential mechanistic differences between wild-type and FTDP-17 tau variants, as well as different tau isoforms, in influencing tau aggregation. Furthermore, by combining two FTDP-17 tau variants (either P301L or P301S with S320F), we generated aggressive models of tauopathy that does not require exogenous seeding. These models will allow for rapid screening of potential therapeutics to alleviate tau aggregation without the need for exogenous tau fibrils. Together, these studies provide novel insights in the molecular determinants that modulate tau aggregation.Tauopathies are a spectrum of neurodegenerative diseases characterized by the presence of pathological inclusions composed of aberrantly aggregated and hyperphosphorylated microtubule-associated protein tau (MAPT). Tauopathies are pathologically and phenotypically diverse, and include Alzheimer's disease (AD), progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, Pick's disease, and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)(1-4). Tau is abundant in neurons and expressed at lower levels in glia (1, 6, 7), and primarily stabilizes microtubules (MTs) among other diverse physiological functions (1,5,8,9). Six different isoforms of tau, ranging from 352 to 441 amino acids, are expressed in the adult human brain as a result of alternative splicing (10, 11). Differential splicing results in the inclusion or exclusion of the R2 MT-binding repeat, producing tau isoforms with either three (3R) or four (4R) repeats, respectively, and one or two N-terminal inserts (Figure 1).Over 50 mutations have been identified in the MAPT gene in families with 2,4,12 Tau Mutants and Seeding 2 disease, and patients typically experience disease onset at ~49 years of age with an average disease duration of 8.5 years (13). Certai...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 83%

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Strang¹,

Croft²,

Sorrentino³

et al. 2018

Journal of Biological Chemistry

104

139

View full text Add to dashboard Cite

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“…Seeding of human tau from homogenates of AD and tauopathies with neuronal and glial components is also observed after inoculation into the brain of wild-type mice [178,179].…”

Section: Disease Progression: Seeding and Spreading; Role Of Astrocytesmentioning

confidence: 93%

Astrogliopathy in Tauopathies

Ferrer

2018

Neuroglia

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Astrocytes are involved in many diseases of the central nervous system, not only as reactive cells to neuronal damage but also as primary actors in the pathological process. Astrogliopathy is a term used to designate the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Astrocytopathy is utilized to name non-reactive astrogliosis covering hypertrophy, atrophy and astroglial degeneration with loss of function in astrocytes and pathological remodeling, as well as senescent changes. Astrogliopathy and astrocytopathy are hallmarks of tauopathies-neurodegenerative diseases with abnormal hyper-phosphorylated tau aggregates in neurons and glial cells. The involvement of astrocytes covers different disease-specific types such as tufted astrocytes, astrocytic plaques, thorn-shaped astrocytes, granular/fuzzy astrocytes, ramified astrocytes and astrocytes with globular inclusions, as well as others which are unnamed but not uncommon in familial frontotemporal degeneration linked to mutations in the tau gene. Knowledge of molecular differences among tau-containing astrocytes is only beginning, and their distinct functional implications remain rather poorly understood. However, tau-containing astrocytes in certain conditions have deleterious effects on neuronal function and nervous system integrity. Moreover, recent studies have shown that tau-containing astrocytes obtained from human brain tauopathies have a capacity for abnormal tau seeding and spreading in wild type mice. Inclusive conceptions include a complex scenario involving neurons, glial cells and local environmental factors that potentiate each other and promote disease progression in tauopathies.

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“…While seeding aggregation with AD brainderived PHFs has been reported in vitro for recombinant Tau (22,23), as well as in vivo (24)(25)(26), it still does not answer whether phosphorylation can drive the initial nucleation of fibers.…”

mentioning

confidence: 99%

Identification of the Tau phosphorylation pattern that drives its aggregation

Despres

Byrne

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

184

190

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Determining the functional relationship between Tau phosphorylation and aggregation has proven a challenge owing to the multiple potential phosphorylation sites and their clustering in the Tau sequence. We use here in vitro kinase assays combined with NMR spectroscopy as an analytical tool to generate well-characterized phosphorylated Tau samples and show that the combined phosphorylation at the Ser202/Thr205/Ser208 sites, together with absence of phosphorylation at the Ser262 site, yields a Tau sample that readily forms fibers, as observed by thioflavin T fluorescence and electron microscopy. On the basis of conformational analysis of synthetic phosphorylated peptides, we show that aggregation of the samples correlates with destabilization of the turn-like structure defined by phosphorylation of Ser202/Thr205.

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Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice

Abstract: Intracerebral inoculation of tau fibrils from AD brains results in the induction and propagation of tau inclusions in WT mice.

Cited by 345 publications

References 61 publications

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies

Astrogliopathy in Tauopathies

Identification of the Tau phosphorylation pattern that drives its aggregation

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