Dataset Information

Amyloidogenic ?-synuclein seeds do not invariably induce rapid, widespread pathology in mice.

ABSTRACT: In order to further evaluate the parameters whereby intracerebral administration of recombinant ?-synuclein (?S) induces pathological phenotypes in mice, we conducted a series of studies where ?S fibrils were injected into the brains of M83 (A53T) and M47 (E46K) ?S transgenic (Tg) mice, and non-transgenic (nTg) mice. Using multiple markers to assess ?S inclusion formation, we find that injected fibrillar human ?S induced widespread cerebral ?S inclusion formation in the M83 Tg mice, but in both nTg and M47 Tg mice, induced ?S inclusion pathology is largely restricted to the site of injection. Furthermore, mouse ?S fibrils injected into nTg mice brains also resulted in inclusion pathology restricted to the site of injection with no evidence for spread. We find no compelling evidence for extensive spread of ?S pathology within white matter tracts, and we attribute previous reports of white matter tract spreading to cross-reactivity of the ?S pSer129/81A antibody with phosphorylated neurofilament subunit L. These studies suggest that, with the exception of the M83 Tg mice which appear to be uniquely susceptible to induction of inclusion pathology by exogenous forms of ?S, there are significant barriers in mice to widespread induction of ?S pathology following intracerebral administration of amyloidogenic ?S.

SUBMITTER: Sacino AN

PROVIDER: S-EPMC4869357 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice.

Sacino Amanda N AN Brooks Mieu M Thomas Michael A MA McKinney Alex B AB McGarvey Nicholas H NH Rutherford Nicola J NJ Ceballos-Diaz Carolina C Robertson Janice J Golde Todd E TE Giasson Benoit I BI

Acta neuropathologica 20140501 5

In order to further evaluate the parameters whereby intracerebral administration of recombinant α-synuclein (αS) induces pathological phenotypes in mice, we conducted a series of studies where αS fibrils were injected into the brains of M83 (A53T) and M47 (E46K) αS transgenic (Tg) mice, and non-transgenic (nTg) mice. Using multiple markers to assess αS inclusion formation, we find that injected fibrillar human αS induced widespread cerebral αS inclusion formation in the M83 Tg mice, but in both ...[more]

PMID: 24659240

Similar Datasets

Project description:MHCII molecules, expressed by professional antigen-presenting cells (APCs) such as T cells and B cells, are hypothesized to play a key role in the response of cellular immunity to α-synuclein (α-syn). However, the role of cellular immunity in the neuroanatomic transmission of α-syn pre-formed fibrillar (PFF) seeds is undetermined. To illuminate whether cellular immunity influences the transmission of α-syn seeds from the periphery into the CNS, we injected preformed α-syn PFFs in the hindlimb of the Line M83 transgenic mouse model of synucleinopathy lacking MhcII. We showed that a complete deficiency in MhcII accelerated the appearance of seeded α-syn pathology and shortened the lifespan of the PFF-seeded M83 mice. To characterize whether B-cell and T-cell inherent MhcII function underlies this accelerated response to PFF seeding, we next injected α-syn PFFs in Rag1-/- mice which completely lacked these mature lymphocytes. There was no alteration in the lifespan or burden of endstage α-syn pathology in the PFF-seeded, Rag1-deficient M83+/- mice. Together, these results suggested that MhcII function on immune cells other than these classical APCs is potentially involved in the propagation of α-syn in this model of experimental synucleinopathy. We focused on microglia next, finding that while microglial burden was significantly upregulated in PFF-seeded, MhcII-deficient mice relative to controls, the microglial activation marker Cd68 was reduced in these mice, suggesting that these microglia were not responsive. Additional analysis of the CNS showed the early appearance of the neurotoxic astrocyte A1 signature and the induction of the Ifnγ-inducible anti-viral response mediated by MhcI in the MhcII-deficient, PFF-seeded mice. Overall, our data suggest that the loss of MhcII function leads to a dysfunctional response in non-classical APCs and that this response could potentially play a role in determining PFF-induced pathology. Collectively, our results identify the critical role of MhcII function in synucleinopathies induced by α-syn prion seeds.

Dataset Information

Amyloidogenic ?-synuclein seeds do not invariably induce rapid, widespread pathology in mice.

Publications

Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets