Abeta Prionenausbreitung im Hirn: Korrelationen mit Verhalten, Prion protein Kofaktor und der Effekt somatischer Mutationen in neuen Tiermodellen
Zusammenfassung der Projektergebnisse
Alzheimer’s disease (AD) is the most common neurodegenerative disease and the Abeta peptide, a processed product of the amyloid precursor protein (APP), easily adopts insoluble conformations that lead to its deposition as extracellular plaques and is generally believed to play a key role in AD pathogenesis. In this research proposal, the regulating influence of soluble Abeta dimers on insoluble Abeta plaques and Abeta prion spreading was investigated in appropriate animal models of AD. We used the tgDimer mouse, a transgenic mouse expressing the human APP gene with both the Swedish mutation and a mutation that links the Abeta peptide with a disulfide bond by introducing the mutation S8C. The tgDimer mouse is a model of early AD, does exclusively express dimeric Abeta and does not deposit Abeta plaques during its lifetime. In a genetic experiment investigating the modulating influence of Abeta dimers to Abeta plaques, tgCRND8 mice exressing human APP with two AD-causing mutations, were crossed to tgDimer mice. The double transgenic mice showed a smaller number of Abeta plaques but the plaques were of similar size. Corroborating these findings, the levels of insoluble Abeta were higher in the tgCRND8 mice as compared to double transgenic mice, and the seeding-inhibiting effect of Abeta S8C dimers was confirmed in a cell-free thioflavin T assay. These results demonstrated that Abeta S8C dimers had an inhibitory effect on Abeta plaque seeds even though they associate to existing plaques. To further investigate whether Abeta dimers also modulate Abeta prion spreading, i.e. the cyclical process of Abeta plaque formation, plaque disintegration and novel seed formation, we inoculated tgDimer mice crossed to tgGFAP-luc mice with homogenates of tgDimer/CRND8 mice. Whereas the positive control, inoculation of tgAPP23/GFAP-luc mice did accelerate the development of Abeta plaques and astrogliosis after month 10 after inoculation, the tgDimer/GFAP-luc mice did not develop astrogliosis and an immunohistochemical analysis did not show Abeta plaques. These results demonstrated that Abeta S8C dimers are antiprions that actively inhibit abeta prion spreading. As a conclusion of this project, Abeta S8C dimers are antiprions in that they inhibit seeding of insoluble Abeta. Even though neurotoxic themselves, Abeta dimers are homologous modulators of Abeta aggregation and their differential regulation by yet unknown factors could account for the heterogeneity of AD neuropathology and clinical disease course.
Projektbezogene Publikationen (Auswahl)
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The interaction of insoluble Amyloid‐β with soluble Amyloid‐β dimers decreases Amyloid‐β plaque numbers. Neuropathology and Applied Neurobiology, 47(5), 603-610.
van Gerresheim Else, F.; Herring, Arne; Gremer, Lothar; Müller‐Schiffmann, Andreas; Keyvani, Kathy & Korth, Carsten
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Soluble amyloid‐β dimers are resistant to amyloid‐β prion conversion in vivo suggesting antiprion properties. Neuropathology and Applied Neurobiology, 49(2).
van Gerresheim Else, F.; Müller‐Schiffmann, Andreas; Schäble, Sandra; Koopmans, Bastijn; Loos, Maarten & Korth, Carsten
