Homoharringtonine Inhibits Alzheimer's Disease Progression by Reducing Neuroinflammation via STAT3 Signaling in APP/PS1 Mice.

Background: Accumulating evidence suggests an implication of neuroinflammation in Alzheimer's disease (AD) pathogenesis. Homoharringtonine (HHT) is an antitumor reagent with anti-inflammatory activity. This study investigates whether and how HHT plays a role in disease progression in a mouse AD model.

Methods: HHT was injected into APP/PS1 mice every other day for 6 months. The effects of HHT on cognitive function were assessed by behavioral assays. β-Amyloid accumulation was assessed by ELISA analysis of Aβ40 and Aβ42. Neuronal loss and synaptic function were determined by levels of NeuN, synaptophysin, and PSD95. Neuroinflammation was assessed by glial markers and pro-inflammatory cytokines. Signal transducer and activator of transcription 3 (STAT3) signaling was evaluated by phosphorylated STAT3 and SOCS3 expression.

Results: We found that HHT at 2 mg/kg significantly alleviated cognitive deficits in APP/PS1 mice. HHT reduced soluble and insoluble Aβ40 and Aβ42 accumulation and attenuated the impairments of synaptic function in the AD mouse hippocampus. Finally, HHT inhibited neuroinflammation, suppressed STAT3 activation, and increased SOCS3 expression in the APP/PS1 mouse hippocampus.

Conclusion: Our results indicate that HHT inhibits disease progression in APP/PS1 mice by suppressing neuroinflammation through modulating the STAT3 signaling. Our findings suggest that HHT may potentially be used for preventing or slowing down AD pathogenesis and warrants further investigation.