Olanzapine attenuates amyloid-ß-induced microglia-mediated progressive neurite lesions.

ABSTRACT

The accumulation of amyloid-ß (Aß) in the brain is the first pathological mechanism to initiate Alzheimer's disease (AD) pathogenesis. However, the precise role of Aß in the disease progression remains unclear. Through decades of research, prolonged inflammation has emerged as an important core pathology in AD. Previously, a study has demonstrated the neurotoxic effect of Aß-induced neuroinflammation in neuron-glia co-culture at 72 h. Here, we hypothesise that initial stage Aß may trigger microglial inflammation, synergistically contributing to the progression of neurite lesions relevant to AD progression. In the present study, we aimed to determine whether olanzapine, an antipsychotic drug possessing anti-inflammatory properties, can ameliorate Aß-induced progressive neurite lesions. Our study reports that Aß induces neurite lesions with or without inflammatory microglial cells in vitro. More intriguingly, the present study revealed that Aß exacerbates neurite lesions in synergy with microglia. Moreover, the time course study revealed that Aß promotes microglia-mediated neurite lesions by eliciting the secretion of pro-inflammatory cytokines. Furthermore, our study shows that olanzapine at lower doses prevents Aß-induced microglia-mediated progressive neurite lesions. The increase in pro-inflammatory cytokines induced by Aß is attenuated by olanzapine administration, associated with a reduction in microglial inflammation. Finally, this study reports that microglial senescence induced by Aß was rescued by olanzapine. Thus, our study provides the first evidence that 1 µM to 5 µM of olanzapine can effectively prevent Aß-induced microglia-mediated progressive neurite lesions by modulating microglial inflammation. These observations reinforce the potential of targeting microglial remodelling to slow disease progression in AD.