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

Background: Soluble amyloid-β oligomer (AβO) 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 AβOs. Understanding the production and spread of toxic AβOs 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 AβOs in AD, were used to identify the specific AβO assembly that contributes to neuronal injury and cognitive deficits. Then, we investigated the production and spread of toxic Aβ assemblies in astrocyte and neuron cultures, and further tested the results following intracerebroventricular injection of AβOs in animal model.

Findings: The results showed that cognitive deficits were mainly caused by the accumulation of nonameric and dodecameric Aβ assemblies in the brains. In addition, we found that the toxic AβOs were duplicated in a time-dependent manner when BACE1 and apolipoprotein E were overexpressed, which were responsible for producing redundant Aβ and forming nonameric and dodecameric assemblies in astrocytes, but not in neurons.

Interpretation: Our results suggest that astrocytes may play a central role in the progression of AD by duplicating and spreading toxic AβOs, thus triggering neuronal injury. FUND: This study was supported by the Key Project of the National Natural Science Foundation of China; the National Key Scientific Instrument and Equipment Development Project; Beijing Scholars Program, and Beijing Brain Initiative from Beijing Municipal Science & Technology Commission.