Abstract
The pathogenesis of Alzheimer’s disease (AD) involves multiple cell types including endothelial cells, glia, and neurons. It suggests that therapy against single target in single cell type may not be sufficient to treat AD and therapies with protective effects in multiple cell types may be more effective. Here, we comprehensively investigated the effects of bilobalide on neuroinflammation and Aβ degrading enzymes in AD cell model and mouse model. We find that bilobalide inhibits Aβ-induced and STAT3-dependent expression of TNF-α, IL-1β, and IL-6 in primary astrocyte culture. Bilobalide also induces robust expression of Aβ degrading enzymes like NEP, IDE, and MMP2 to facilitate astrocyte-mediated Aβ clearance. Moreover, bilobalide treatment of astrocyte rescues neuronal deficiency in co-cultured APP/PS1 neurons. Most importantly, bilobalide reduces amyloid and inflammation in AD mouse brain. Taken together, the protective effects of bilobalide in in vitro cultures were fully recapitulated in in vivo AD mouse model. Our study supports that bilobalide has therapeutic potential for AD treatment.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive deterioration in cognition and daily function [1]
We find that bilobalide inhibits Aβ-induced and STAT3-dependent expression of TNF-α, IL-1β, and IL-6 in primary astrocyte culture
We report that bilobalide acts on astrocytes to inhibit STAT3-depednet expression of inflammation cytokines and promotes the expression of Aβ degrading enzymes to rescue neuronal deficiency in in vitro and in vivo AD models
Summary
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by progressive deterioration in cognition and daily function [1]. The key pathological changes observed in AD brain tissue are amyloid-β (Aβ) peptide deposited as extracellular plaques and hyperphosphorylated tau (p-tau) accumulated as intracellular neurofibrillary tangles (NFTs). Additional changes include reactive gliosis and widespread loss of neurons and synapses. AD is a complex and progressive neurodegenerative disorder, and multiple cell types were involved in its pathogenesis including endothelial cells, glia and neurons [2, 3]. Most clinical trials in AD patients have failed and it suggests that therapies against single target in single cell type may not be sufficient to treat AD. Therapies with protective effects in multiple cell types may be more effective
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