In situ structural biology of pathological protein deposits in Alzheimer's disease

Bashit, Abdullah Al; Connors, Theresa R.; Nepal, Prakash; Vallon, Matthew; Deravi, Leila F.; Yang, Lin; Oakley, Derek H.; Hyman, Bradley T.; Makowski, Lee

doi:10.1016/j.bpj.2021.11.1955

Cited by 1 publication

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“…Analysis of the equatorial scattering can provide information about the diameter and shape of the fibrils and the arrangement of material around the fibril within the tissue (Roig Solvas and Makowski, 2017). Comparison of the shape of the 4.7 Å reflection with that predicted from high resolution structures obtained by cryoEM studies of isolated or in vitro-assembled material may provide identification of the precise structure within the scattering volume (Bashit et al, 2022). In this report, we limit our analysis to the smallangle regime.…”

Section: Fiber Diffractionmentioning

confidence: 99%

“…Scattering from the non-fibrillar tissue constituents is removed from fibrillar scattering within the plaque by assuming that the scattering of the tissue constituents within the lesion is the same as in a neighboring region devoid of fibrils. Since scattering from the underlying mica substrate does not require scaling, we carried out subtraction according to I = (Il -Ib) -a (It -Ib) where Il is the observed scattering from the lesion; It that observed from proximal tissue; Ib background observed from scattering from mica devoid of tissue (Bashit et al, 2022). The scale factor, a, is chosen to minimize the difference between plaque and background intensities in the range 1.6 < q < 2.0 Å -1 , where all evidence has indicated the fibrillar scattering is weak.…”

Section: Background Subtractionmentioning

confidence: 99%

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Small-angle x-ray microdiffraction from fibrils embedded in tissue thin sections

Nepal

Bashit

Yang

et al. 2022

Preprint

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Small-angle x-ray scattering (SAXS) from fibrils embedded in a fixed, thin section of tissue includes contributions from the fibrils; the polymeric matrix surrounding the fibrils; other constituents of the tissue; and cross-terms due to the spatial correlation between fibrils and neighbouring molecules. This complex mixture severely limits the amount of information that can be extracted from scattering studies. However, availability of micro- and nano-beams has made possible measurement of scattering from very small volumes which, in some cases, may be dominated by a single fibrillar constituent. In those cases, information about the predominant species may be accessible. Nevertheless, even in these cases, the correlations between the positions of fibrils and other constituents have significant impact on the observed scattering. Here, we propose strategies to extract partial information about fibril structure and tissue organization on the basis of SAXS from samples of this type. We show that the spatial correlation function of the fibril in the direction perpendicular to the fibril axis can be computed and contains information about the predominant fibril structure and the organization of the surrounding tissue matrix. It has significant advantages over approaches based on techniques developed for x-ray solution scattering. We present examples of the calculation of correlation in different types of samples to demonstrate the kinds of information that can be obtained from these measurements.SynopsisThe availability of micro- and nano- x-ray beams is making possible measurement of scattering from very small volumes, opening possibilities for derivingin situstructural information on fibrillar constituents in complex materials and tissues. This work outlines a set of strategies for confronting the formidable technical obstacles to extracting useful structural information from scattering derived from these materials.

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Section: Fiber Diffractionmentioning

confidence: 99%

Section: Background Subtractionmentioning

confidence: 99%