Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons. Autophagy is a powerful process for removing such proteins. In this Review, we consider how certain neurodegenerative diseases may be associated with impaired autophagy and how this may affect pathology. We also discuss how autophagy induction may be a plausible therapeutic strategy for some conditions and review studies in various models that support this hypothesis. Finally, we briefly describe some of the signaling pathways that may be amenable to therapeutic targeting for these goals.

Autophagy and neurodegeneration

Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there’s a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases. Previous studies showed that balancing microglia M1/M2 polarization had a promising therapeutic prospect in neurodegenerative diseases. We suggest that shifting microglia from M1 to M2 may be significant and we focus on the modulation of microglia polarization from M1 to M2, especially by important signal pathways, in neurodegenerative diseases.

Microglia Polarization From M1 to M2 in Neurodegenerative Diseases

Melatonin, an indoleamine hormone produced and secreted at night by pinealocytes and extra-pineal cells, plays an important role in timing circadian rhythms (24-h internal clock) and regulating the sleep/wake cycle in humans. However, in recent years melatonin has gained much attention mainly because of its demonstrated powerful lipophilic antioxidant and free radical scavenging action. Melatonin has been proven to be twice as active as vitamin E, believed to be the most effective lipophilic antioxidant. Melatonin-induced signal transduction through melatonin receptors promotes the expression of antioxidant enzymes as well as inflammation-related genes. Melatonin also exerts an immunomodulatory action through the stimulation of high-affinity receptors expressed in immunocompetent cells. Here, we reviewed the efficacy, safety and side effects of melatonin supplementation in treating oxidative stress- and/or inflammation-related disorders, such as obesity, cardiovascular diseases, immune disorders, infectious diseases, cancer, neurodegenerative diseases, as well as osteoporosis and infertility.

Is Melatonin the Cornucopia of the 21st Century

Modern societies are experiencing an increasing trend of reduced sleep duration, with nocturnal sleeping time below the recommended ranges for health. Epidemiological and laboratory studies have demonstrated detrimental effects of sleep deprivation on health. Sleep exerts an immune-supportive function, promoting host defense against infection and inflammatory insults. Sleep deprivation has been associated with alterations of innate and adaptive immune parameters, leading to a chronic inflammatory state and an increased risk for infectious/inflammatory pathologies, including cardiometabolic, neoplastic, autoimmune and neurodegenerative diseases. Here, we review recent advancements on the immune responses to sleep deprivation as evidenced by experimental and epidemiological studies, the pathophysiology, and the role for the sleep deprivation-induced immune changes in increasing the risk for chronic diseases. Gaps in knowledge and methodological pitfalls still remain. Further understanding of the causal relationship between sleep deprivation and immune deregulation would help to identify individuals at risk for disease and to prevent adverse health outcomes.

Role of sleep deprivation in immune-related disease risk and outcomes.

New research has shown that the development of osteoarthritis (OA) is regulated by different mechanisms of cell death and types of cytokines. Therefore, elucidating the mechanism of action among various cytokines, cell death processes and OA is important towards better understanding the pathogenesis and progression of the disease. This paper reviews the pathogenesis of OA in relation to different types of cytokine-triggered cell death. We describe the cell morphological features and molecular mechanisms of pyroptosis, apoptosis, necroptosis, and ferroptosis, and summarize the current research findings defining the molecular mechanisms of action between different cell death types and OA.

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Targeting Cell Death: Pyroptosis, Ferroptosis, Apoptosis and Necroptosis in Osteoarthritis

With aging, the nervous system gradually undergoes degeneration. Increased oxidative stress, endoplasmic reticulum stress, mitochondrial dysfunction, and cell death are considered to be common pathophysiological mechanisms of various neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), organophosphate-induced delayed neuropathy (OPIDN), and amyotrophic lateral sclerosis (ALS). Autophagy is a cellular basic metabolic process that degrades the aggregated or misfolded proteins and abnormal organelles in cells. The abnormal regulation of neuronal autophagy is accompanied by the accumulation and deposition of irregular proteins, leading to changes in neuron homeostasis and neurodegeneration. Autophagy exhibits both a protective mechanism and a damage pathway related to programmed cell death. Because of its "double-edged sword", autophagy plays an important role in neurological damage and NDDs including AD, PD, HD, OPIDN, and ALS. Melatonin is a neuroendocrine hormone mainly synthesized in the pineal gland and exhibits a wide range of biological functions, such as sleep control, regulating circadian rhythm, immune enhancement, metabolism regulation, antioxidant, anti-aging, and anti-tumor effects. It can prevent cell death, reduce inflammation, block calcium channels, etc. In this review, we briefly discuss the neuroprotective role of melatonin against various NDDs via regulating autophagy, which could be a new field for future translational research and clinical studies to discover preventive or therapeutic agents for many NDDs.

https://www.mdpi.com/1422-0067/21/19/7174/pdf

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by loss of recognition and memory. Neuroinflammation plays pivotal roles in the pathology of AD and affects the progression of the disease. Astrocyte and microglia, as main immune executors in the central nervous system (CNS), participate into the inflammatory response in AD. Glia polarize into different phenotypes during neurodegeneration. Pro-inflammatory glia produce cytokines (IL-1β, TNF-α, and IL-6) resulting into debris aggregates and neurotoxicity. Anti-inflammatory phenotypes produce cytokines (IL-4 and IL-10) to release the inflammation. Electroacupuncture is a useful treatment that has been found to slow the neurodegeneration in animals through experimentation and in humans through clinical trials. The aim of this study was to uncover the mechanisms of glia activation, microglia polarization, and cytokine secretion regulated by electroacupuncture as a treatment for AD.

Methods: Twenty male Sprague–Dawley (SD) rats were randomly divided into four groups: Control group (Control), Normal saline group (NS), AD group (AD), and Electroacupuncture group (Acupuncture). The AD and Acupuncture groups were bilaterally injected with Aβ1–42 into the CA1 field of the hippocampus. The Acupuncture group received electroacupuncture stimulation on the acupoint “Baihui” (GV20) for 6 days per week for a total of 3 weeks. The Morris Water Maze (MWM) was used to evaluate learning and memory capacity. Immunofluorescence was used to stain GFAP and Iba1 of the DG and CA1 in the hippocampus, which, respectively, expressed the activation of astrocyte and microglia. The M1 microglia marker, inducible nitric oxide synthase (iNOS), and M2 marker Arginase 1 (Arg1) were used to analyze the polarization of microglia. The pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), anti-inflammatory cytokines (IL-4 and IL-10), and pathway-molecules (p65 and Stat6) were tested to analyze the glia inflammatory response by immunofluorescence and polymerase chain reaction (PCR).

Results: The MWM results showed that electroacupuncture improves the escape latency time and the swimming distance of AD rats. The number of GFAP and Iba1 cells significantly increased in AD rats, but electroacupuncture decreased the cells. The iNOS-positive cells were significantly increased in AD, and electroacupuncture decreased the positive cells. Electroacupuncture elevated Arg1-positive cells in AD rats. Electroacupuncture decreased the glia pro-inflammatory cytokine expression and increased the anti-inflammatory cytokine expression in AD rats. Furthermore, electroacupuncture inhibited the NF-κB pathway molecule (p65) while raising the Stat6 pathway molecule (Stat6).

Conclusion: These results provide evidence that electroacupuncture improves the recognition abilities and memory of AD rats. Electroacupuncture inhibits the activation of glia and polarizes microglia toward the M2 phenotype. Electroacupuncture decreased the pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and increased the anti-inflammatory cytokines (IL-4 and IL-10). Furthermore, electroacupuncture affects the immune responses through inhibition of NF-κB pathway but activation of Stat6 pathway.

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Electroacupuncture Improves M2 Microglia Polarization and Glia Anti-inflammation of Hippocampus in Alzheimer's Disease.

The increasing comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) associated with traumatic brain injury (TBI) is a serious medical, economic, and social issue. However, the molecular toxicology and pathophysiological mechanisms of comorbid AUD and PTSD are not well understood and the identification of the comorbidity state markers is significantly challenging. This review summarizes the main characteristics of comorbidity between AUD and PTSD (AUD/PTSD) and highlights the significance of a comprehensive understanding of the molecular toxicology and pathophysiological mechanisms of AUD/PTSD, particularly following TBI, with a focus on the role of metabolomics, inflammation, neuroendocrine, signal transduction pathways, and genetic regulation. Instead of a separate disease state, a comprehensive examination of comorbid AUD and PTSD is emphasized by considering additive and synergistic interactions between the two diseases. Finally, we propose several hypotheses of molecular mechanisms for AUD/PTSD and discuss potential future research directions that may provide new insights and translational application opportunities.

https://www.mdpi.com/1422-0067/24/10/8805/pdf?version=1684199355

Aaron F. Sandhu

Papers

Melatonin and Autophagy in Aging-Related Neurodegenerative Diseases

Electroacupuncture Improves M2 Microglia Polarization and Glia Anti-inflammation of Hippocampus in Alzheimer's Disease.

Molecular Toxicology and Pathophysiology of Comorbid Alcohol Use Disorder and Post-Traumatic Stress Disorder Associated with Traumatic Brain Injury