Localization of fibrillar polymorphs in human brain tissue Summary Fibrillar aggregates of A? peptides and tau protein are defining features of Alzheimer's disease (AD) but the role these structures play in the etiology of disease remains uncertain. High resolution cryo-electron microscopy (cryo-EM) and solid-state NMR (ssNMR) have been used to generate a host of molecular models of fibrillar polymorphs, some or all of which may be relevant to disease. These structural models have provided the foundation for studies demonstrating an association of specific polymorphs with different disease subtypes. Outstanding questions remain as to the distribution of polymorphs between and within cases. The proposed work will apply, in situ, a structural technique that has resolution higher than immunostaining; is very sensitive to amyloid structure; can distinguish between fibrillar polymorphs; and keeps anatomical and spatial relationships intact. Preliminary data show that it can probe both tangles and plaques in intact unstained tissue. In agreement with other techniques, these data indicate that there are polymorphs of A? structure between and within cases. Analogous associations have yet to be demonstrated for tau deposits, and those associations will be tested here. The central hypothesis of the proposed work is that the spatial distribution of structural polymorphs in brain tissue will provide important clues as to how fibrils contribute to disease. In the proposed studies, X-ray microdiffraction (XMD) of histological sections of brain tissue will be used to map the locations of fibrillar polymorphs of both A? and tau, generating sub-cellular (~ 5 ?? resolution maps of polymorph abundances across millimeter-scale regions of interest. Initial work (Specific Aim 1) will map the distribution of A? and tau polymorphs in human brain tissue in sporadic AD cases, including samples from several brain regions. These results will be compared (Specific Aim 2) to analogous results from (i) MAPT mutant cases, (ii) PS1 cases and to (iii) cases of occipital predominant visuo-spatial AD. Comparison to MAPT mutants will demonstrate whether tau fibrils with distinct molecular morphologies exhibit preservation of conformational signatures during disease spread; comparison with PS1 cases will provide analogous information for A? fibrils; comparison with occipital predominant visuo-spatial AD will probe fibrillar conformations and polymorph distributions in disease with distinctly different patterns of progression. The results of these studies will provide a preliminary assessment of whether or not different fibrillar polymorphs spread by a prion-like process during disease progression and provide insights into the mechanisms by which different strains are associated with different disease subtypes.
Fibrillar protein aggregates are defining features of Alzheimer's disease. Many variants of these fibrils have been studied, but their role in disease progression remains uncertain. In this project, the distribution of different types of fibrils in the brain will be studied to better understand the way they contribute to disease.
