Virtual histology of Alzheimer's disease: Biometal entrapment within amyloid-β plaques allows for detection via X-ray phase-contrast imaging

Amyloid- beta (A beta) 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 A beta plaques. The current study was designed to test the hypothesis that A beta-related contrast in XPCT could be caused by A beta fibrils and/or by metals trapped in the plaques. Fibrillar and elemental compositions of A beta plaques were probed 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 (one genetic and one sporadic case) 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 those from the sporadic AD patient, which remained undetected by XPCT. A beta plaques in J20 mice and TgF344 rats appeared hyperdense on XPCT images, while they were hypodense with a hyperdense 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 hyperdense contrast formation of A beta plaques in XPCT images was associated with biometal entrapment within plaques.

Automated summary

Synchrotron X-ray phase-contrast tomography (XPCT) can visualize amyloid-beta (A beta) plaques from Alzheimer's Disease (AD) in label-free brain samples. This study suggests that the contrast of A beta in XPCT may be caused by A beta fibrils and/or metals trapped in the plaques. Analysis of brain samples from different types of AD patients and AD models reveals that a hyperdense contrast formation of A beta plaques in XPCT images is associated with biometal entrapment within plaques.