Virtual histology of Alzheimer's Disease: why are amyloid-β plaques visible with X-ray phase-contrast imaging?

Amyloid-{beta} (A{beta}) plaques from Alzheimers 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 A{beta} plaques. The current study was designed to test the hypothesis that A{beta}-related contrast in XPCT could be caused by the A{beta} fibrils and/or by metals trapped in the plaques. This study probed the fibrillar and elemental compositions of A{beta} plaques in brain samples from different types of AD patients and AD models to establish a relationship between XPCT contrast and A{beta} 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, ArcA{beta}, J20; rat: TgF344). A{beta} plaques from the genetic AD patient were visible using XPCT, and had higher {beta}-sheet content and higher metal levels than the sporadic AD patient, which remained undetected by XPCT. A{beta} 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 ArcA{beta} mice. In all four transgenic strains, {beta}-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 ArcA{beta} mice. Hence, a positive contrast formation of A{beta} plaques in XPCT images appeared driven by biometal entrapment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/509706v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@56e672org.highwire.dtl.DTLVardef@1336d85org.highwire.dtl.DTLVardef@15b6690org.highwire.dtl.DTLVardef@1aaa6cb_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAmyloid-{beta} plaques in the different forms of Alzheimers Disease have various contrasts in X-ray phase-contrast tomography C_LIO_LIIn transgenic rodents, a core-restricted, positive contrast is driven by the level of metal entrapment within plaques C_LIO_LIIn humans, greater and more diffuse metal accumulation lead to a positive contrast in a genetic case of AD C_LI