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

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 Aβ fibrils and/or by metals trapped in the plaques. Fibrillar and elemental compositions of Aβ plaques were probed 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 (one genetic and one sporadic case) 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 those from the sporadic AD patient, which remained undetected by XPCT. Aβ 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 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 hyperdense contrast formation of Aβ plaques in XPCT images was associated with biometal entrapment within plaques. STATEMENT OF SIGNIFICANCE: The role of metals in Alzheimer's disease (AD) has been a subject of continuous interest. It was already known that amyloid-β plaques (Aβ), the earliest hallmark of AD, tend to trap endogenous biometals like zinc, iron and copper. Here we show that this metal accumulation is the main reason why Aβ plaques are detected with a new technique called X-ray phase contrast tomography (XPCT). XPCT enables to map the distribution of Aβ plaques in the whole excised brain without labeling. In this work we describe a unique collection of four transgenic models of AD, together with a human sporadic and a rare genetic case of AD, thus exploring the full spectrum of amyloid contrast in XPCT.