Abstract
Amyloid β-peptide (Aβ) is directly linked to Alzheimer's disease (AD). In its monomeric form, Aβ aggregates to produce fibrils and a range of oligomers, the latter being the most neurotoxic. Dysregulation of Ca2+ homeostasis in aging brains and in neurodegenerative disorders plays a crucial role in numerous processes and contributes to cell dysfunction and death. Here we postulated that calcium may enable or accelerate the aggregation of Aβ. We compared the aggregation pattern of Aβ(1–40) and that of Aβ(1–40)E22G, an amyloid peptide carrying the Arctic mutation that causes early onset of the disease. We found that in the presence of Ca2+, Aβ(1–40) preferentially formed oligomers similar to those formed by Aβ(1–40)E22G with or without added Ca2+, whereas in the absence of added Ca2+ the Aβ(1–40) aggregated to form fibrils. Morphological similarities of the oligomers were confirmed by contact mode atomic force microscopy imaging. The distribution of oligomeric and fibrillar species in different samples was detected by gel electrophoresis and Western blot analysis, the results of which were further supported by thioflavin T fluorescence experiments. In the samples without Ca2+, Fourier transform infrared spectroscopy revealed conversion of oligomers from an anti-parallel β-sheet to the parallel β-sheet conformation characteristic of fibrils. Overall, these results led us to conclude that calcium ions stimulate the formation of oligomers of Aβ(1–40), that have been implicated in the pathogenesis of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects nearly 2% of the population in industrialized countries
Protofibrils and apparently some fibrils were detectable at the top portion of the gel
In the absence of added Ca2+, amyloid b-peptide (Ab)(1–40) molecules had aggregated to such an extent that we were able to detect only bands with low electrophoretic mobility corresponding mainly to high-molecular-weight oligomers, protofibrils and fibrils, located in or near the stacking part of the polyacrylamide gel (Fig.1A, two last lanes)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects nearly 2% of the population in industrialized countries. The pathologic hallmark of AD was attributed to the continuous accumulation of amyloid b-peptide (Ab) fibrils into plaques. Their toxic effects on synaptic connections and neurons were explained by the amyloid cascade hypothesis [1]. Experiments aimed at establishing a direct causal relationship between Ab deposition and the neurodegeneration that underlies AD dementia failed [2,3]. This apparent discrepancy between plaque burden and neuronal dysfunction has been described in transgenic mouse models of AD [4,5]. Results of studies that focused on the electrophysiological impact of Ab oligomers suggested that the underlying memory loss is caused by rapid inhibition of long-term potentiation (LTP)—a classical model for synaptic plasticity and memory mechanisms [11]—by oligomers [12,13,14], which might explain, at least in part, the mild cognitive impairment observed in the early stages of AD [9]
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