One of the most striking hallmarks shared by various neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis, is microglia-mediated ...neuroinflammation. Increasing evidence indicates that microglial activation in the central nervous system is heterogeneous, which can be categorized into two opposite types: M1 phenotype and M2 phenotype. Depending on the phenotypes activated, microglia can produce either cytotoxic or neuroprotective effects. In this review, we focus on the potential role of M1 and M2 microglia and the dynamic changes of M1/M2 phenotypes that are critically associated with the neurodegenerative diseases. Generally, M1 microglia predominate at the injury site at the end stage of disease, when the immunoresolution and repair process of M2 microglia are dampened. This phenotype transformation is very complicated in AD due to the phagocytosis of regionally distributed β-amyloid (Aβ) plaque and tangles that are released into the extracellular space. The endogenous stimuli including aggregated α-synuclein, mutated superoxide dismutase, Aβ, and tau oligomers exist in the milieu that may persistently activate M1 pro-inflammatory responses and finally lead to irreversible neuron loss. The changes of microglial phenotypes depend on the disease stages and severity; mastering the stage-specific switching of M1/M2 phenotypes within appropriate time windows may provide better therapeutic benefit.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system (CNS), which affects mostly older adults. In recent years, the incidence of PD has been ...dramatically increasing with the aging population expanding. Due to the lack of effective biomarkers, the accurate diagnosis and precise treatment of PD are currently compromised. Notably, metabolites have been considered as the most direct reflection of the physiological and pathological conditions in individuals and represent attractive candidates to provide deep insights into disease phenotypes. By profiling the metabolites in biofluids (cerebrospinal fluid, blood, urine), feces and brain tissues, metabolomics has become a powerful and promising tool to identify novel biomarkers and provide valuable insights into the etiopathogenesis of neurological diseases. In this review, we will summarize the recent advancements of major analytical platforms implemented in metabolomics studies, dedicated to the improvement and extension of metabolome coverage for in-depth biological research. Based on the current metabolomics studies in both clinical populations and experimental PD models, this review will present new findings in metabolomics biomarkers research and abnormal metabolic pathways in PD, and will discuss the correlation between metabolomic changes and clinical conditions of PD. A better understanding of the biological underpinning of PD pathogenesis might offer novel diagnostic, prognostic, and therapeutic approaches to this devastating disease.
The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular ...machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy‐related pathways as therapeutic targets for the treatment of these diseases.
Summary Iron homeostasis requires the regulation of iron influx, iron efflux and iron storage, which are all essential to the execution of the multiple functions of the central nervous system. ...Abnormal accumulation of iron in the brain has been implicated in several neurodegenerative diseases, including Parkinson's disease (PD) and neurodegeneration with brain iron accumulation (NBIA). Although the cause of the neurodegenerative process in PD remains unclear, recent evidence suggests that failure of the ubiquitin-proteasome system (UPS) may play an important role in the pathogenesis of this disease. Our studies have shown that injection of the proteasome inhibitor lactacystin in the substantia nigra (SN) of rodents causes significant loss of dopamine (DA) neurons and induces intracellular inclusion body formation, which is accompanied by excessive iron accumulation in the midbrain. In the in vitro model, lactacystin causes a marked increase in labile iron, reactive oxygen species, alteration of iron regulatory protein (IRP)/iron response element expression levels, and an increase in the aggregation of ubiquitin-conjugated proteins prior to cell injury and death. Furthermore, we have demonstrated that synthetic iron chelators and a genetic iron chelator are neuroprotective against proteasome inhibitor-induced DA neuron degeneration, suggesting that iron chelation might be a promising therapeutic target for PD.
Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell ...survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis （MS）, a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system （CNS）. Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis （EAE, a mouse model of MS）. Dysfunction of mitochondria that intensively influences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene （ATG） 5 and immune-related GTPase M （IRGM） 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin （mTOR）, ameliorates relapsing-remitting EAE. Inflammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-11/LC3-1 ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-inflammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinflammation associated with the pathogenesis of MS.
The majority cases of Alzheimer's disease (AD) are sporadic late-onset form not being linked to APP and PS1 gene mutations. It is believed that the environmental risk factors play an important role ...in the onset and development of AD. Patients suffering from cerebral ischemia and stroke in which hypoxic conditions occur are much more susceptible to AD. Increasing evidence suggests that hypoxia facilitates the pathogenesis of AD through accelerating the accumulation of Aβ, increasing the hyperphosphorylation of tau, impairing the normal functions of blood–brain barrier, and promoting the degeneration of neurons. Further investigations into the relationship between hypoxia and AD may open the avenue for effective preservation and pharmacological treatments of this neurodegenerative disease.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few ...decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.
Stem cells are unspecialized cells that have the potential for self-renewal and differentiation into more specialized cell types. The chemical and physical properties of surrounding microenvironment ...contribute to the growth and differentiation of stem cells and consequently play crucial roles in the regulation of stem cells' fate. Nanomaterials hold great promise in biological and biomedical fields owing to their unique properties, such as controllable particle size, facile synthesis, large surface-to-volume ratio, tunable surface chemistry, and biocompatibility. Over the recent years, accumulating evidence has shown that nanomaterials can facilitate stem cell proliferation and differentiation, and great effort is undertaken to explore their possible modulating manners and mechanisms on stem cell differentiation. In present review, we summarize recent progress in the regulating potential of various nanomaterials on stem cell differentiation and discuss the possible cell uptake, biological interaction and underlying mechanisms.
Major depressive disorder （MDD） is a complicated multifactorial induced disease, characterized by depressed mood, anhedonia, fatigue, and altered cognitive function. Recently, many studies have shown ...that antidepressants regulate autophagy. In fact, autophagy, a conserved lysosomal degradation pathway, is essential for the central nervous system. Dysregulation of autophagic pathways, such as the mammalian target of rapamycin （mTOR） signaling pathway and the beclin pathway, has been studied in neurodegenerative diseases. However, autophagy in MDD has not been fully studied. Here, we discuss whether the dysregulation of autophagy contributes to the pathophysiology and treatment of MDD and summarize the current evidence that shows the involvement of autophagy in MDD.
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