Amyloid Beta-Protein Fibrils from Human Alzheimer's Brain Tissue and from Mouse Models of Alzheimer's Differ in Structures

Abstract

Electron microscopy (EM) and two dimensional infrared spectroscopy have shown that the molecular structure of amyloid fibrils prepared in vitro from synthetic 40-residue amyloid β-protein (Aβ40), are not uniquely determined by the amino acid sequence of Aβ40. Instead, fibril structure can vary depending on growth conditions. Therefore, the suitability of fibrils from mouse models of Alzheimer's disease (AD) as models of fibrils that form in human AD is uncertain. In this study, fibrils extracted from brain tissue of three different human AD patients were used to seed the growth of synthetic Aβ40 fibrils. Because amyloid fibril structures self-propagate via seeded growth, the structure of seeded Aβ40 fibrils is likely to reflect the structure of fibrils formed in AD brain. Mass-per-length (MPL) measurements derived from dark-field transmission EM images indicate that the most prevalent number of filaments in human-fibril-seeded-fibrils is 3, with a secondary peak at 2 filaments per fibril. The same result was obtained from all three cases of human AD, but it differs from MPL measurements on Aβ40 fibrils seeded with extracted fibrils from the brain tissue of mouse models of AD (three strains of aged transgenic mice, 3xTg, J20 and 5xFAD), in which there are 3, 4 and 5 filaments per fibril. Moreover, the most prevalent number can vary among mice of the same strain. We conclude that amyloid fibrils in mouse models of AD and fibrils from human AD are fundamentally different in structure.