Metal Ions Differentially Influence the Aggregation and Deposition of Alzheimer's β-Amyloid on a Solid Template

Abstract

The abnormal deposition and aggregation of beta-amyloid (Abeta) on brain tissues are considered to be one of the characteristic neuropathological features of Alzheimer's disease (AD). Environmental conditions such as metal ions, pH, and cell membranes are associated with Abeta deposition and plaque formation. According to the amyloid cascade hypothesis of AD, the deposition of Abeta42 oligomers as diffuse plaques in vivo is an important earliest event, leading to the formation of fibrillar amyloid plaques by the further accumulation of soluble Abeta under certain environmental conditions. In order to characterize the effect of metal ions on amyloid deposition and plaque growth on a solid surface, we prepared a synthetic template by immobilizing Abeta oligomers onto a N-hydroxysuccinimide ester-activated solid surface. According to our study using ex situ atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FT-IR), and thioflavin T (ThT) fluorescence spectroscopy, Cu2+ and Zn2+ ions accelerated both Abeta40 and Abeta42 deposition but resulted only in the formation of "amorphous" aggregates. In contrast, Fe3+ induced the deposition of "fibrillar" amyloid plaques at neutral pH. Under mildly acidic environments, the formation of fibrillar amyloid plaques was not induced by any metal ion tested in this work. Using secondary ion mass spectroscopy (SIMS) analysis, we found that binding Cu ions to Abeta deposits on a solid template occurred by the possible reduction of Cu ions during the interaction of Abeta with Cu2+. Our results may provide insights into the role of metal ions on the formation of fibrillar or amorphous amyloid plaques in AD.

Substoichiometric Levels of Cu2+ Ions Accelerate the Kinetics of Fiber Formation and Promote Cell Toxicity of Amyloid-β from Alzheimer Disease

“…Based on TEM images, under these conditions, the morphology of the fibers generated appears quite similar for fibers formed with and without the presence of Cu 2ϩ ions. We note that previous studies by other groups using TEM did not reveal fibers in the presence of Cu 2ϩ because the high A␤ and Cu 2ϩ concentrations used caused amorphous precipitation (42)(43)(44)(45)(46). Furthermore, the Cu 2ϩ -generated fibers are capable of seeding fiber formation of fresh, metal-free A␤ as indicated by a reduction in the lag time (see supplemental Fig.…”

“…These initial studies did not make the distinction between amorphous aggregates, which are nontoxic to cells, and the formation of amyloid fibers. Further investigations using the fiber specific fluorophore thioflavin T (ThT) suggested that Zn 2ϩ and Cu 2ϩ only promote amorphous aggregation of A␤ and actually inhibit fiber formation and cell toxicity (42)(43)(44)(45)(46). We became interested in the factors that promote self-association of A␤, the relationship between amorphous aggregation and amyloid fiber formation, and a role for Cu 2ϩ ions in promoting fiber formation.…”

Site-Specific Blockade of RAGE-VdPrevents Amyloid-β Oligomer Neurotoxicity

“…The mechanism by which A␤ aggregates is not fully understood, although it has been shown that peptide concentration, ions, pH, and temperature influence the A␤ oligomerization process and fibril conversion (Isaacs et al, 2006;Ha et al, 2007). In the present study, we generated two conditioned media (RPMI and Neurobasal) containing 10 M analogs of soluble A␤Os, A␤Fs, or amorphous A␤As.…”

Geniposide Induces the Expression of Heme Oxygenase-1 via PI3K/Nrf2-Signaling to Enhance the Antioxidant Capacity in Primary Hippocampal Neurons

“…24) Briefly, the core promoter sequence of human ho-1 (-56 to -206) was cloned from the human genome and inserted into pGL3-Basic vector (Promega). Further, the AB1 enhancer-like sequence of human ho-1 was amplified using the primer Fw-Ab1: 5-GCTAGCTAATCCTTTCCCGAGCCA-3, Rv-Ab1: 5-GCTGGATATCTGAGGAAAAC-3.…”