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Traditional Chinese Medicine: Role in Reducing ?-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer’s Disease.

ABSTRACT: Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The major characteristics of AD are amyloid ? plaques, apoptosis, autophagy dysfunction, neuroinflammation, oxidative stress, and mitochondrial dysfunction. These are mostly used as the significant indicators for selecting the effects of potential drugs. It is imperative to explain AD pathogenesis and realize productive treatments. Although the currently used chemical drugs for clinical applications of AD are effective in managing the symptoms, they are inadequate to achieve anticipated preventive or therapeutic outcomes. There are new strategies for treating AD. Traditional Chinese Medicine (TCM) has accumulated thousands of years of experience in treating dementia. Nowadays, numerous modern pharmacological studies have verified the efficacy of many bioactive ingredients isolated from TCM for AD treatment. In this review, representative TCM for the treatment of AD are discussed, and among these herbal medicines, the Lamiaceae family accounts for the highest proportion. It is concluded that monomers and extracts from TCM have potential therapeutic effect for AD treatment.

SUBMITTER: Chen S

PROVIDER: S-EPMC7188934 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:Alzheimer’s Disease (AD) is the 6th leading cause of death in the US. It is established that neuroinflammation contributes to the synaptic loss, neuronal death, and symptomatic decline of AD patients. Accumulating evidence suggests a critical role for microglia, innate immune phagocytes of the brain. For instance, microglia release pro-inflammatory products such as IL-1β which is highly implicated in AD pathobiology. The mechanisms underlying the transition of microglia to proinflammatory promoters of AD remain largely unknown. To address this gap, we performed Representation Bisulfite Sequencing (RRBS) to profile global DNA methylation changes in human AD brains compared to no disease controls. We identified differential DNA methylation of CASPASE-4 (CASP4), which when expressed, can be involved in generation of IL-1β and is predominantly expressed in immune cells. DNA upstream of the CASP4 transcription start site was hypomethylated in human AD brains, which was correlated with increased expression of CASP4. Furthermore, microglia from a mouse model of AD (5xFAD) express increased levels of CASP4 compared to wild-type (WT) mice. To study the role of CASP4 in AD, we developed a novel mouse model of AD lacking CASP4 (5xFAD/Casp4-/-). The expression of CASP4 was associated with increased accumulation of pathologic protein aggregate amyloid-β (Aβ) in 5xFAD mice. Utilizing RNA sequencing, we determined that CASP4 promotes unique transcriptomic phenotypes in 5xFAD mouse brains, including alterations of neuroinflammatory and chemokine signaling pathways. Notably, in vitro, CASP4 promoted generation of IL-1β from macrophages and microglia in response to cytosolic Aβ through cleavage of downstream effector GASDERMIN-D (GSDMD). We are the first to describe a role for CASP4 and GSDMD in the generation of IL-1β in response to Aβ and the progression of pathologic inflammation in AD. Overall, our results demonstrate that overexpression of CASP4 due to differential methylation in AD microglia contributes to the progression of AD pathobiology, thus identifying CASP4 as a potential target for immunotherapies for the treatment of AD.

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Traditional Chinese Medicine: Role in Reducing ?-Amyloid, Apoptosis, Autophagy, Neuroinflammation, Oxidative Stress, and Mitochondrial Dysfunction of Alzheimer’s Disease.

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