Amyloid plaques in PSAPP mice bind less metal than plaques in human Alzheimer's disease

Abstract

Amyloid beta (Abeta) is the primary component of Alzheimer's disease (AD) plaques, a key pathological feature of the disease. Metal ions of zinc (Zn), copper (Cu), iron (Fe), and calcium (Ca) are elevated in human amyloid plaques and are thought to be involved in neurodegeneration. Transgenic mouse models of AD also exhibit amyloid plaques, but fail to exhibit the high degree of neurodegeneration observed in humans. In this study, we imaged the Zn, Cu, Fe, and Ca ion distribution in the PSAPP transgenic mouse model representing end-stage AD (N=6) using synchrotron X-ray fluorescence (XRF) microprobe. In order to account for differences in density in the plaques, the relative protein content was imaged with synchrotron Fourier transform infrared microspectroscopy (FTIRM) on the same samples. FTIRM results revealed a 61% increase in protein content in the plaques compared to the surrounding tissue. After normalizing to protein density, we found that the PSAPP plaques contained only a 29% increase in Zn and there was actually less Cu, Fe, and Ca in the plaque compared to the surrounding tissue. Since metal binding to Abeta is thought to induce redox chemistry that is toxic to neurons, the reduced metal binding in PSAPP mice is consistent with the lack of neurodegeneration in these animals. These findings were in stark contrast to the high metal ion content observed in human AD plaques, further implicating the role of metal ions in human AD pathology.

Figure 1

(A) Thioflavin S-stained PSAPP mouse brain tissue showing three plaques. (B) Infrared image of the same tissue showing the distribution of protein measured by the Amide II band. (C) Infrared spectra collected from the areas marked with asterisks in (A) and (B), showing the relative amount of protein in the center of a plaque (black) and the surrounding tissue (red). All scale bars are 5 μm.

Figure 2

(A) Thioflavin S-stained PSAPP mouse brain tissue, also shown in Fig. 1. XRF microprobe images of (B) Zn, (C) Cu, (D) Fe, and (E) Ca distribution in the same tissue. (F) XRF microprobe spectra collected from the areas marked with asterisks in (A) – (E), comparing the center of a plaque (black) to the surrounding tissue (red). All scale bars are 5 μm.