Dataset Information

Seeded strain-like transmission of ?-amyloid morphotypes in APP transgenic mice.

ABSTRACT: The polymorphic ?-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral ?-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop ?-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and A?40/A?42 peptide ratio. To determine the nature of such ?-amyloid morphotypes, ?-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally injected into the hippocampus of young APP23 or APPPS1 transgenic mice. APPPS1 brain extract injected into young APP23 mice induced ?-amyloid deposition with the morphological, conformational, and A?40/A?42 ratio characteristics of ?-amyloid deposits in aged APPPS1 mice, whereas APP23 brain extract injected into young APP23 mice induced ?-amyloid deposits with the characteristics of ?-amyloid deposits in aged APP23 mice. Injecting the two extracts into the APPPS1 host revealed a similar difference between the induced ?-amyloid deposits, although less prominent, and the induced deposits were similar to the ?-amyloid deposits found in aged APPPS1 hosts. These results indicate that the molecular composition and conformation of aggregated A? in APP transgenic mice can be maintained by seeded conversion.

SUBMITTER: Heilbronner G

PROVIDER: S-EPMC3818077 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice.

Heilbronner Götz G Eisele Yvonne S YS Langer Franziska F Kaeser Stephan A SA Novotny Renata R Nagarathinam Amudha A Aslund Andreas A Hammarström Per P Nilsson K Peter R KP Jucker Mathias M

EMBO reports 20130903 11

The polymorphic β-amyloid lesions present in individuals with Alzheimer's disease are collectively known as cerebral β-amyloidosis. Amyloid precursor protein (APP) transgenic mouse models similarly develop β-amyloid depositions that differ in morphology, binding of amyloid conformation-sensitive dyes, and Aβ40/Aβ42 peptide ratio. To determine the nature of such β-amyloid morphotypes, β-amyloid-containing brain extracts from either aged APP23 brains or aged APPPS1 brains were intracerebrally inje ...[more]

PMID: 23999102

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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

Seeded strain-like transmission of ?-amyloid morphotypes in APP transgenic mice.

Publications

Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice.

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