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Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer's Disease.

ABSTRACT: Rehmanniae Radix (RR, the dried tuberous roots of Rehmannia glutinosa (Gaertn.) DC.) is an important traditional Chinese medicine distributed in Henan, Hebei, Inner Mongolia, and Northeast in China. RR is frequently used to treat diabetes mellitus, cardiovascular disease, osteoporosis and aging-related diseases in a class of prescriptions. The oligosaccharides and catalpol in RR have been confirmed to have neuroprotective effects. However, there are few studies on the anti-Alzheimer's disease (AD) effect of oligosaccharides in Rehmanniae Radix (ORR). The chemical components and pharmacological effects of dried Rehmannia Radix (DRR) and prepared Rehmannia Radix (PRR) are different because of the different processing methods. ORR has neuroprotective potential, such as improving learning and memory in rats. Therefore, this study aimed to prove the importance of oligosaccharides in DRR (ODRR) and PRR (OPRR) for AD based on the Caenorhabditis elegans (C. elegans) model and the different roles of ODRR and OPRR in the treatment of AD. In this study, we used paralysis assays, lifespan and stress resistance assays, bacterial growth curve, developmental and behavioral parameters, and ability of learning and memory to explore the effects of ODRR and OPRR on anti-AD and anti-aging. Furthermore, the accumulation of reactive oxygen species (ROS); deposition of Aβ; and expression of amy-1, sir-2.1, daf-16, sod-3, skn-1, and hsp-16.2 were analyzed to confirm the efficacy of ODRR and OPRR. OPRR was more effective than ODRR in delaying the paralysis, improving learning ability, and prolonging the lifespan of C. elegans. Further mechanism studies showed that the accumulation of ROS, aggregation, and toxicity of Aβ were reduced, suggesting that ORR alleviated Aβ-induced toxicity, in part, through antioxidant activity and Aβ aggregation inhibiting. The expression of amy-1 was downregulated, and sir-2.1, daf-16, sod-3, and hsp-16.2 were upregulated. Thus, ORR could have a possible therapeutic effect on AD by modulating the expression of amy-1, sir-2.1, daf-16, sod-3, and hsp-16.2. Furthermore, ORR promoted the nuclear localization of daf-16 and further increased the expression of sod-3 and hsp-16.2, which significantly contributed to inhibiting the Aβ toxicity and enhancing oxidative stress resistance. In summary, the study provided a new idea for the development of ORR.

SUBMITTER: Kang N

PROVIDER: S-EPMC9247152 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The deposition of ?-sheet rich amyloid in senile plaques is a pathological hallmark of Alzheimer's disease (AD), which is thought to cause neuronal dysfunction. Previous studies have strongly implicated that intracerebral infusion of brain extract containing aggregated ?-amyloid (A?) is able to induce cerebral amyloidosis thus causing neuronal damage and clinical abnormalities in rodents and nonhuman primates, which are reminiscent of a prion-like mechanism. Prion disease has been documented in cases of prion-contaminated food consumption. Methods: We investigated whether cerebral transmission of A? was possible via oral administration of A?-rich brain extract in non-susceptible and susceptible host mice by immunohistochemistry, western blotting and behavior tests. Also brain extracts were supplied to AD transgenic Caenorhabditis elegans, and paralysis curve were conducted, following detection of A? amyloid. RNA sequencing of nematodes was applied then inhibitors for relevant dysregulated genes were used in the paralysis induction. Results: The oral treatment of AD brain extract or normal brain extract neither aggravated nor mitigated the A? load, glial activation or the abnormal behaviors in recipient Amyloid precursor protein/presenilin 1 (APP/PS1) mice. Whereas, a significant improvement of AD pathology was detected in worms treated with A?-rich or normal brain extracts, which was attributable to the heat-sensitive components of brain extracts. Transcriptome sequencing of CL4176 nematodes suggested that brain extracts could delay worm paralysis through multiple pathways, including ubiquitin mediated proteolysis and Transforming growth factor ? (TGF-?) signaling pathway. Inhibitors of the ubiquitin proteasome system and the TGF-? signaling pathway significantly blocked the suppressive effects of brain extracts on worm paralysis. Conclusions: Our results suggest that systemic transmissible mechanisms of prion proteopathy may not apply to ? amyloid, at least in terms of oral administration. However, brain extracts strongly ameliorated AD pathology in AD transgenic nematodes partially through TGF-? signaling pathway and ubiquitin mediated proteolysis, which indicated that some natural endogenous components in the mammalian tissues could resist A? toxicity.

Project description:Palmatine is a naturally occurring isoquinoline alkaloid that has been reported to display neuroprotective effects against amyloid-β- (Aβ-) induced neurotoxicity. However, the mechanisms underlying the neuroprotective activities of palmatine remain poorly characterized in vivo. We employed transgenic Caenorhabditis elegans models containing human Aβ 1-42 to investigate the effects and possible mechanisms of palmatine-mediated neuroprotection. Treatment with palmatine significantly delayed the paralytic process and reduced the elevated reactive oxygen species levels in Aβ-transgenic C. elegans. In addition, it increased oxidative stress resistance without affecting the lifespan of wild-type C. elegans. Pathway analysis suggested that the differentially expressed genes were related mainly to aging, detoxification, and lipid metabolism. Real-time PCR indicated that resistance-related genes such as sod-3 and shsp were significantly upregulated, while the lipid metabolism-related gene fat-5 was downregulated. Further studies demonstrated that the inhibitory effects of palmatine on Aβ toxicity were attributable to the free radical-scavenging capacity and that the upregulated expression of resistance-related genes, especially shsp, whose expression was regulated by HSF-1, played crucial roles in protecting cells from Aβ-induced toxicity. The research showed that there were significantly fewer Aβ deposits in transgenic CL2006 nematodes treated with palmatine than in control nematodes. In addition, our study found that Aβ-induced toxicity was accompanied by dysregulation of lipid metabolism, leading to excessive fat accumulation in Aβ-transgenic CL4176 nematodes. The alleviation of lipid disorder by palmatine should be attributed not only to the reduction in fat synthesis but also to the inhibition of Aβ aggregation and toxicity, which jointly maintained metabolic homeostasis. This study provides new insights into the in vivo neuroprotective effects of palmatine against Aβ aggregation and toxicity and provides valuable targets for the prevention and treatment of AD.

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Neuroprotective Effects of Oligosaccharides in Rehmanniae Radix on Transgenic Caenorhabditis elegans Models for Alzheimer's Disease.

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