ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease that currently cannot be cured by any drug or intervention, due to its complicated pathogenesis. Current animal and cellular models of AD are unable to meet research needs for AD. However, recent three-dimensional (3D) cerebral organoid models derived from human stem cells have provided a new tool to study molecular mechanisms and pharmaceutical developments of AD. In this review, we discuss the advantages and key limitations of the AD cerebral organoid system in comparison to the commonly used AD models, and propose possible solutions, in order to improve their application in AD research. Ethical concerns associated with human cerebral organoids are also discussed. We also summarize future directions of studies that will improve the cerebral organoid system to better model the pathological events observed in AD brains.
Subject(s)
Alzheimer Disease/pathology , Biomedical Research/trends , Brain/pathology , Models, Biological , Organoids/pathology , Alzheimer Disease/metabolism , Animals , Biomedical Research/methods , Brain/metabolism , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Organoids/metabolism , Protein FoldingABSTRACT
Women experience cognitive decline as they age due to the decrease in estrogen levels following menopause. Currently, effective pharmaceutical treatments for agerelated cognitive decline are lacking; however, several Traditional Chinese medicines have shown promising effects. Lycium barbarum polysaccharides (LBPs) were found to exert a wide variety of biological activities, including antiinflammatory, antioxidant and antiaging effects. However, to the best of our knowledge, the neuroprotective actions of LBP on cognitive impairment induced by decreased levels of estrogen have not yet been determined. To evaluate the effects of LBP on learning and memory impairment in an animal model of menopause, 45 female ICR mice were randomly divided into the following three groups: i) Sham; ii) ovariectomy (OVX); and iii) OVX + LBP treatment. The results of openfield and novel object recognition tests revealed that mice in the OVX group had learning and memory impairments, and lacked the ability to recognize and remember new objects. Notably, these deficits were attenuated following LBP treatment. Immunohistochemical staining confirmed the protective effects of LBP on hippocampal neurons following OVX. To further investigate the underlying mechanism of OVX in mice, mRNA sequencing of the hippocampal tissue was performed, which revealed that the Tolllike receptor 4 (TLR4) inflammatory signaling pathway was significantly upregulated in the OVX group. Moreover, reverse transcriptionquantitative PCR and immunohistochemical staining demonstrated that OVX induced hippocampal injury, upregulated the expression levels of TLR4, myeloid differentiation factor 88 and NFκB, and increased the expression of TNFα, IL6 and IL1ß inflammatory factors. Conversely, LBP treatment downregulated the expression levels of mRNAs and proteins associated with the TLR4/NFκB signaling pathway, decreased the inflammatory response and reduced neuronal injury in mice that underwent OVX. In conclusion, the findings of the present study indicated that oral LBP treatment may alleviate OVXinduced cognitive impairments by downregulating the expression levels of mRNAs and proteins associated with the TLR4/NFκB signaling pathway, thereby reducing neuroinflammation and damage to the hippocampal neurons. Thus, LBP may represent a potential agent for the prevention of learning and memory impairments in patients with accelerated aging caused by estrogen deficiency.
Subject(s)
Aging/drug effects , Drugs, Chinese Herbal/pharmacology , Memory Disorders/drug therapy , Neurocognitive Disorders/drug therapy , Signal Transduction/drug effects , Administration, Oral , Animals , Female , Gene Expression Regulation , Hippocampus/drug effects , Learning/drug effects , Medicine, Chinese Traditional , Mice , Mice, Inbred ICR , NF-kappa B/genetics , NF-kappa B/metabolism , Neuroinflammatory Diseases/drug therapy , Neurons/drug effects , Ovariectomy/adverse effects , Random Allocation , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolismABSTRACT
The chaperone protein heat shock protein 60 (HSP60) is considered a tumor promoter in several types of primary human tumors, where it orchestrates a broad range of survival programs. Curcumin (CCM) is well-established to exhibit several anticancer properties with an excellent safety profile. Our previous study showed that CCM suppresses extracellular HSP60 expression, which is typically released by activated microglia, and acts as an inflammatory factor by binding to Toll-like receptor 4 (TLR-4) on the cell membrane. The present study assessed whether CCM exerted its anti-neuroglioma effects on U87 cells via inhibition of HSP60/TLR-4 signaling, similar to that in microglia. The results demonstrated that CCM significantly inhibited the viability and invasive capacity of neuroglioma U87 cells as evidenced by a Cell Counting Kit-8 assay. Western blotting and ELISA results showed that CCM decreased the expression of HSP60 and its transcriptional factor, heat shock factor 1, and reduced HSP60 release. Accordingly, TLR-4, as the target of HSP60, and its downstream signaling proteins myeloid differentiation primary response 88 (MYD88), NF-κB, inducible nitric oxide synthase and cytokines IL-1ß and IL-6 were downregulated by CCM. The expression levels of apoptotic factors associated with NF-κB activation, including TNF-α and caspase-3 were increased in U87 cells by CCM treatment, while p53 expression, a tumor suppressor, was shown to be decreased. Based on the results of the present study, CCM may exert its anti-tumor effects in U87 cells by inhibiting the HSP60/TLR-4/MYD88/NF-κB pathway and inducing tumor cell apoptosis. Thus, CCM may be used as a potential therapy for the clinical treatment of neuroglioma.
