The Study On The Effect And Mechanism Of Oridonin On The Cognitive Dysfunction Of Mouse Model Of Alzheimer’s Disease

Background:Alzheimer’s disease (AD), as the major cause of dementia, is a progressive and fatal neurodegenerative disease with progressive memory impairment and cognitive dysfunction. The typical pathological features of AD compose of beta-amyloid (Aβ) plaques (accumulation of extracellular Aβ) and neurofibrillary tangles (NFTs, deposition of intracellular hyperphosphorylated tau protein). The Aβ cascade hypothesis has been thought as the key mechanism of AD, emerging evidence suggests that the loss of synapses and neuroinflammation induced by Aβ are involved in the pathology of AD.Objectives:The aims of this study are:1) to confirm the effects of Oridonin (Ori) on cognitive dysfunction of AD mouse model; 2) to investigate the role of Ori on Aβ1-42-induced synaptic loss and its mechanism; 3) to study the role of Ori on Aβ1-42-induced neuroinflammation and its mechanism.Methods:(1) The i.c.v microinjections of Aβ1-42 into the bilateral hippocampus of male C57BL/6 (B6) mice to make the AD mouse model, Aβ1-42 treated primary cortical neurons to make the vitro model of AD. The Morris water maze was used to assess the role of Ori on the cognitive of AD mice. (2) The expression of PSD-95 and synaptophysin in vitro and in vivo was measured by Western blot and immunostaining. The synaptosome activity was assessed by MTT. The morphology of dendritic spines in the brain was analyzed using Golgi staining. Western blot and immunostaining was used to examine whether Ori activate the BDNF/TrkB/CREB signaling pathway. (3) The expression of pro-inflammatory factors was determined by RT-PCR and Western blot. The activation of microglia and astrocytes was tested by immunostaining. Western blot was used to measure the dysfunction of mitochondrial and the activation of NF-κB signaling pathway.Results:(1) Ori improved cognitive deficits in Aβ1-induced AD mice. Ori increased the expression of PSD-95 and synaptophysin in the hippocampus of AD mice and Aβ1-42 treated neurons. Ori rescued the dendritic morphological changes in the hippocampus of AD mice. In addition, Ori increased the expression of PSD-95 and synaptophysin and promoted mitochondrial activity in the synaptosomes of AD mice. Furthermore, Ori treatment enhanced the BDNF/TrkB/CREB signaling pathway in the hippocampus of AD mice. (2) Ori inhibited the release of pro-inflammatory factors in the hippocampus of Aβ1-42-induced AD mice and decreased microglia and astrocytes activation in the hippocampus of AD mice. Furthermore, Ori inhibited Aβ1-42-induced activation of NF-κB signaling pathway and decreased mitochondrial injury in the hippocampus of AD mice.Conclusion:Our findings suggested that Ori improved cognitive deficits in Aβ1-42-induced AD mice, the potential mechanism could be associated with attenuating the synaptic loss and neuroinflammation in the hippocampus of AD mice. Therefore, Ori might be a potential drug that targets synapses and neuroinflammation for the treatment of AD.