Why are amyloid-β plaques detected by X-ray phase-contrast imaging? Role of metals revealed through combined synchrotron infrared and X-ray fluorescence microscopies

Abstract Amyloid-β (Aβ) plaques from Alzheimer’s Disease (AD) can be visualized ex vivo in label-free brain samples using synchrotron X-ray phase-contrast tomography (XPCT). However, for XPCT to be useful as a screening method for amyloid pathology, it is essential to understand which factors drive the detection of Aβ plaques. The current study was designed to test the hypothesis that Aβ-related contrast in XPCT could be caused by the Aβ fibrils and/or by metals trapped in the plaques. This study probed the fibrillar and elemental compositions of Aβ plaques in brain samples from different types of AD patients and AD models to establish a relationship between XPCT contrast and Aβ plaque characteristics. XPCT, micro-Fourier-Transform Infrared spectroscopy and micro-X-Ray Fluorescence spectroscopy were conducted on human samples (genetic and sporadic cases) and on four transgenic rodent strains (mouse: APPPS1, ArcAβ, J20; rat: TgF344). Aβ plaques from the genetic AD patient were visible using XPCT, and had higher β–sheet content and higher metal levels than the sporadic AD patient, which remained undetected by XPCT. Aβ plaques in J20 mice and TgF344 rats appeared hyperintense on XPCT images, while they were hypointense with an hyperintense core in the case of APPPS1 and ArcAβ mice. In all four transgenic strains, β-sheet content was similar, while metal levels were highly variable: J20 (zinc and iron) and TgF344 (copper) strains showed greater metal accumulation than APPPS1 and ArcAβ mice. Hence, a positive contrast formation of Aβ plaques in XPCT images appeared driven by biometal entrapment. Graphical Abstract Highlights Amyloid-β plaques in the different forms of Alzheimer’s Disease have various contrasts in X-ray phase-contrast tomography In transgenic rodents, a core-restricted, positive contrast is driven by the level of metal entrapment within plaques In humans, greater and more diffuse metal accumulation lead to a positive contrast in a genetic case of AD