Project 1 Prusiner There is increasing evidence from both cell culture and animal models that both the A peptide and the tau protein become self-propagating in Alzheimer's disease (AD), initiating a cascade of neurodegeneration that spreads throughout the brain, indicating that A and tau are prions. Thus, the molecular events underlying the pathogenesis of AD and tauopathies are reminiscent of Creutzfeldt-Jakob disease (CJD), in which the misfolding of the prion protein (PrP) into a self-templating isoform termed PrPSc initiates disease. However, to better understanding the structural and biochemical properties of self-propagating protein aggregates in AD requires the creation of cellular and animal bioassays capable of rapidly ascertaining the presence of these prions. We propose to study three different human prions composed of PrPSc, A or tau, each of which cause age-dependent neurodegeneration. In these studies, we will take advantage of new paradigms that allows us to monitor disease progression and to diagnose neurodegeneration in living mice, in addition to novel cellular assays, greatly accelerating research efforts.
In Aim 1 we will build on our recent observation that Tg(APP23) can propagate different A strains. We propose to identify A strain diversity from both natural and synthetic sources, both by bioassay and in cell culture. We also plan to generate new transgenic rat models.
In Aim 2 we attempt to create a better models of sporadic and genetic human prion diseases by a combination of cell culture and transgenic mouse studies, based on studies demonstrating that bank vole PrP can faithfully propagate human prion strains.
In Aim 3, we will investigate a cell model of intracellular tau aggregation to develop a cellular bioassay for tau prions using confocal fluorescence microscopy.
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| Condello, Carlo; Lemmin, Thomas; Stöhr, Jan et al. (2018) Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease. Proc Natl Acad Sci U S A 115:E782-E791 |
| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135:49-63 |
| Yang, Bing; Wu, Haifan; Schnier, Paul D et al. (2018) Proximity-enhanced SuFEx chemical cross-linker for specific and multitargeting cross-linking mass spectrometry. Proc Natl Acad Sci U S A 115:11162-11167 |
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| Woerman, Amanda L; Watts, Joel C; Aoyagi, Atsushi et al. (2018) ?-Synuclein: Multiple System Atrophy Prions. Cold Spring Harb Perspect Med 8: |
| Woerman, Amanda L; Kazmi, Sabeen A; Patel, Smita et al. (2018) Familial Parkinson's point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci U S A 115:409-414 |
| Wang, Tuo; Jo, Hyunil; DeGrado, William F et al. (2017) Water Distribution, Dynamics, and Interactions with Alzheimer's ?-Amyloid Fibrils Investigated by Solid-State NMR. J Am Chem Soc 139:6242-6252 |
| Giles, Kurt; Woerman, Amanda L; Berry, David B et al. (2017) Bioassays and Inactivation of Prions. Cold Spring Harb Perspect Biol 9: |
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