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Differential cross-seeding properties of tau and ?-synuclein in mouse models of tauopathy and synucleinopathy.

ABSTRACT: Co-occurrence of tau and ?-synuclein pathologies in a subset of Alzheimer's disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer's disease neurodegenerative cascade. To understand the aetiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant ?-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of tau fibrils or ?-synuclein fibrils, and to a lesser extent tau?+??-synuclein copolymer fibrils prepared from co-incubating individual recombinant monomers, induced robust phosphorylated tau pathology in PS19 mice relative to control mice. Though the tau?+??-synuclein copolymer fibrils did not modulate induction of pathologies at the site of injection, examination of the whole brain showed that these copolymers exacerbated neuroanatomic transmission of seeded tau pathology compared to tau fibril-injected mice. Only ?-synuclein fibrils, but not tau alone or tau?+??-synuclein copolymers, triggered modest levels of endogenous phosphorylated ?-synuclein pathology. Overall, data from the PS19 mice suggest that human ?-synuclein fibrils can efficiently cross-seed human tau and have a modest priming effect on mouse ?-synuclein, and the presence of tau fibrils does not exacerbate the priming process. In M20 mice, unilateral hippocampal injection of ?-synuclein fibrils or tau fibrils induced robust bilateral phosphorylated ?-synuclein pathology, while tau?+??-synuclein copolymer injection resulted in restricted phosphorylated ?-synuclein pathology predominantly in the ipsilateral cortex. This suggests that human tau fibrils can also induce human ?-synuclein pathogenesis, and the presence of combinatorial seeds is not synergistic. None of these aggregates induced phosphorylated tau pathology in M20 mice, showing that mouse tau cannot be primed efficiently by human tau fibrils or human ?-synuclein fibrils. Neuropathological analysis of the whole brain of M20 mice showed that tau?+??-synuclein copolymer-injected mice had lower abundance of bilaterally transmitted ?-synuclein pathologies relative to ?-synuclein fibril-injected mice. Thus, the tau?+??-synuclein copolymer fibrils show robust transmission properties preferentially in rodent model of tauopathies but not in synucleinopathy, probably signifying an enhanced cooperative relationship between tau and ?-synuclein in the tau seeding process. Together, our data highlight the unique cross-seeding properties of tau and ?Syn in neurodegenerative proteinopathies.

SUBMITTER: Williams T

PROVIDER: S-EPMC7567170 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Differential cross-seeding properties of tau and α-synuclein in mouse models of tauopathy and synucleinopathy.

Williams Tosha T Sorrentino Zachary Z Weinrich Mary M Giasson Benoit I BI Chakrabarty Paramita P

Brain communications 20200703 2

Co-occurrence of tau and α-synuclein pathologies in a subset of Alzheimer's disease patients has led to the idea that mixed pathologies may play a unique characteristic role in the Alzheimer's disease neurodegenerative cascade. To understand the aetiology of such mixed pathologies, we investigated cross-seeding by human recombinant tau and human recombinant α-synuclein fibrillar species in a mouse model of tauopathy (Line PS19) or synucleinopathy (Line M20). Unilateral hippocampal injection of t ...[more]

PMID: 33094280

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Project description:Tauopathies are neurodegenerative disorders characterized by aggregation of microtubule associated tau protein in neurons and glia. They are clinically and pathologically heterogeneous depending on the isoform of tau protein that accumulates (three or four 31-to-32-amino-acid repeats [3R or 4R] in the microtubule binding domain), as well as the cellular and neuroanatomical distribution of tau pathology. Growing evidence suggests that distinct tau conformers may contribute to the characteristic features of various tauopathies. Globular glial tauopathy (GGT) is a rare 4R tauopathy with globular cytoplasmic inclusions within neurons and glial cells. Given the unique cellular distribution and morphology of tau pathology in GGT, we sought to determine if tau species in GGT had distinctive biological properties. To address this question, we performed seeding analyses with postmortem brain tissues using a commercial tau biosensor cell line. We found that brain lysates from GGT cases had significantly higher seeding competency than other tauopathies, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). The robust seeding activity of GGT brain lysates was independent of phosphorylated tau burden and diminished upon removal of tau from samples, suggesting that seeding properties were indeed mediated by tau in the lysates. In addition, cellular inclusions in the tau biosensor cell line induced by GGT had a distinct, globular morphology that was markedly different from inclusions induced by other tauopathies, further highlighting the unique nature of tau species in GGT. Characterization of different tau species in GGT showed that detergent-insoluble, fibril-like tau contained the highest seeding activity, as reflected in its ability to increase tau aggregation in primary glial cultures. Taken together, our data suggest that unique seeding properties differentiate GGT-tau from other tauopathies, which provides new insight into pathogenic heterogeneity of primary neurodegenerative tauopathies.

Dataset Information

Differential cross-seeding properties of tau and ?-synuclein in mouse models of tauopathy and synucleinopathy.

Publications

Differential cross-seeding properties of tau and α-synuclein in mouse models of tauopathy and synucleinopathy.

Similar Datasets

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