Toxic amyloid-β oligomers induced self-replication in astrocytes triggering neuronal injury

Background: Soluble amyloid-beta oligomer (A beta O) induced deleterious cascades have recently been considered to be the initiating pathologic agents of Alzheimer's disease (AD). However, little is known about the neurotoxicity and production of different A beta Os. Understanding the production and spread of toxic A beta Os within the brain is important to improving understanding of AD pathogenesis and treatment. Methods: Here, PS1V97L transgenic mice, a useful tool for studying the role of A beta Os in AD, were used to identify the specific A beta O assembly that contributes to neuronal injury and cognitive deficits. Then, we investigated the production and spread of toxic A beta assemblies in astrocyte and neuron cultures, and further tested the results following intracerebroventricular injection of A beta Os in animal model. Findings: The results showed that cognitive deficits were mainly caused by the accumulation of nonameric and dodecameric A beta assemblies in the brains. In addition, we found that the toxic A beta Os were duplicated in a time-dependent manner when BACE1 and apolipoprotein E were overexpressed, which were responsible for producing redundant A beta and forming nonameric and dodecameric assemblies in astrocytes, but not in neurons. Interpretation: Our results suggest that astrocytesmay play a central role in the progression of AD by duplicating and spreading toxic A beta Os, thus triggering neuronal injury.