How brain 'cleaners' fail: Mechanisms and therapeutic value of microglial phagocytosis in Alzheimer's disease.

Microglia are the resident phagocytes of the brain, where they primarily function in the clearance of dead cells and the removal of un- or misfolded proteins. The impaired activity of receptors or proteins involved in phagocytosis can result in enhanced inflammation and neurodegeneration. RNA-seq and genome-wide association studies have linked multiple phagocytosis-related genes to neurodegenerative diseases, while the knockout of such genes has been demonstrated to exert protective effects against neurodegeneration in animal models. The failure of microglial phagocytosis influences AD-linked pathologies, including amyloid ß accumulation, tau propagation, neuroinflammation, and infection. However, a precise understanding of microglia-mediated phagocytosis in Alzheimer's disease (AD) is still lacking. In this review, we summarize current knowledge of the molecular mechanisms involved in microglial phagocytosis in AD across a wide range of pre-clinical, post-mortem, ex vivo, and clinical studies and review the current limitations regarding the detection of microglia phagocytosis in AD. Finally, we discuss the rationale of targeting microglial phagocytosis as a therapeutic strategy for preventing AD or slowing its progression.

Zinc finger protein 335 mediates lipopolysaccharide-induced neurodegeneration and memory loss as a transcriptional factor in microglia.

Zinc finger protein 335 (Zfp335) is a transcription factor that regulates mammalian neurogenesis and neuronal differentiation. It is a causative factor for severe microcephaly, small somatic size, and neonatal death. Here, we evaluated the effects of Zfp335 in the adult mouse brain after lipopolysaccharide (LPS) challenge. We used wild-type (WT) and Zfp335 knock-down (Zfp335+/- ) mice with LPS administered in the intracerebral ventricle in vivo and cultured microglia treated with LPS in vitro. The impact of Zfp335 was evaluated by RT-PCR, RNA-sequencing, western blotting, immunocytochemistry, ELISA, and the memory behavior tests. Knockdown of Zfp335 expression ameliorated microglia activation significantly, including reduced mRNA and protein expression of Iba1, reduced numbers of microglia, reduced cell diameter, and increased branch length, in the brains of 2-month-old mice after LPS treatment. Zfp335 was expressed in microglia and neurons, but increased in microglia, not neurons, in the brain of mice after LPS administration. LPS-induced microglia-mediated neurodegeneration was dependent upon microglial Zfp335 controlled by nuclear factor-kappa B. Microglial Zfp335 affected neuronal activity through transcriptional regulation of lymphocyte antigen-6M (Ly6M). Our data suggest that Zfp335 is a key transcription factor that exacerbates microglia-mediated neurodegeneration through upregulation of Ly6M expression. Inhibition of microglial Zfp335 may be a new strategy for preventing brain disease induced by microglia activation.

Appropriate Macronutrients or Mineral Elements Are Beneficial to Improve Depression and Reduce the Risk of Depression.

Depression is a common mental disorder that seriously affects the quality of life and leads to an increasing global suicide rate. Macro, micro, and trace elements are the main components that maintain normal physiological functions of the brain. Depression is manifested in abnormal brain functions, which are considered to be tightly related to the imbalance of elements. Elements associated with depression include glucose, fatty acids, amino acids, and mineral elements such as lithium, zinc, magnesium, copper, iron, and selenium. To explore the relationship between these elements and depression, the main literature in the last decade was mainly searched and summarized on PubMed, Google Scholar, Scopus, Web of Science, and other electronic databases with the keywords "depression, sugar, fat, protein, lithium, zinc, magnesium, copper, iron, and selenium". These elements aggravate or alleviate depression by regulating a series of physiological processes, including the transmission of neural signals, inflammation, oxidative stress, neurogenesis, and synaptic plasticity, which thus affect the expression or activity of physiological components such as neurotransmitters, neurotrophic factors, receptors, cytokines, and ion-binding proteins in the body. For example, excessive fat intake can lead to depression, with possible mechanisms including inflammation, increased oxidative stress, reduced synaptic plasticity, and decreased expression of 5-Hydroxytryptamine (5-HT), Brain Derived Neurotrophic Factor (BDNF), Postsynaptic density protein 95(PSD-95), etc. Supplementing mineral elements, such as selenium, zinc, magnesium, or lithium as a psychotropic medication is mostly used as an auxiliary method to improve depression with other antidepressants. In general, appropriate nutritional elements are essential to treat depression and prevent the risk of depression.

The Role of Oxytocin in Early-Life-Stress-Related Neuropsychiatric Disorders.

Early-life stress during critical periods of brain development can have long-term effects on physical and mental health. Oxytocin is a critical social regulator and anti-inflammatory hormone that modulates stress-related functions and social behaviors and alleviates diseases. Oxytocin-related neural systems show high plasticity in early postpartum and adolescent periods. Early-life stress can influence the oxytocin system long term by altering the expression and signaling of oxytocin receptors. Deficits in social behavior, emotional control, and stress responses may result, thus increasing the risk of anxiety, depression, and other stress-related neuropsychiatric diseases. Oxytocin is regarded as an important target for the treatment of stress-related neuropsychiatric disorders. Here, we describe the history of oxytocin and its role in neural circuits and related behaviors. We then review abnormalities in the oxytocin system in early-life stress and the functions of oxytocin in treating stress-related neuropsychiatric disorders.

Role of Vitronectin and Its Receptors in Neuronal Function and Neurodegenerative Diseases.

Vitronectin (VTN), a multifunctional glycoprotein with various physiological functions, exists in plasma and the extracellular matrix. It is known to be involved in the cell attachment, spreading and migration through binding to the integrin receptor, mainly via the RGD sequence. VTN is also widely used in the maintenance and expansion of pluripotent stem cells, but its effects go beyond that. Recent evidence shows more functions of VTN in the nervous system as it participates in neural differentiation, neuronutrition and neurogenesis, as well as in regulating axon size, supporting and guiding neurite extension. Furthermore, VTN was proved to play a key role in protecting the brain as it can reduce the permeability of the blood-brain barrier by interacting with integrin receptors in vascular endothelial cells. Moreover, evidence suggests that VTN is associated with neurodegenerative diseases, such as Alzheimer's disease, but its function has not been fully understood. This review summarizes the functions of VTN and its receptors in neurons and describes the role of VTN in the blood-brain barrier and neurodegenerative diseases.

Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway.

Rab21 is a GTPase protein that is functional in intracellular trafficking and involved in the pathologies of many diseases, such as Alzheimer's disease (AD), glioma, cancer, etc. Our previous work has reported its interaction with the catalytic subunit of gamma-secretase, PS1, and it regulates the activity of PS1 via transferring it from the early endosome to the late endosome/lysosome. However, it is still unknown how Rab21 protein itself is regulated. This work revealed that Rab21 protein, either endogenously or exogenously, can be degraded by the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. It is further observed that the ubiquitinated Rab21 is increased, but the total protein is unchanged in AD model mice. We further observed that overexpression of Rab21 leads to increased expression of a series of genes involved in the autophagy-lysosome pathway. We speculated that even though the ubiquitinated Rab21 is increased due to the impaired proteasome function in the AD model, the autophagy-lysosome pathway functions in parallel to degrade Rab21 to keep its protein level in homeostasis. In conclusion, understanding the characters of Rab21 protein itself help explore its potential as a target for therapeutic strategy in diseases.

Optogenetic manipulation of astrocytes from synapses to neuronal networks: A potential therapeutic strategy for neurodegenerative diseases.

Astrocytes are the most widespread and heterogeneous glial cells in the central nervous system and key regulators for brain development. They are capable of receiving neurotransmitters produced by synaptic activities and regulating synaptic functions by releasing gliotransmitters as part of the tripartite synapse. In addition to communicating with neurons at synaptic levels, astrocytes can integrate into inhibitory neural networks to interact with neurons in neuronal circuits. Astrocytes are closely related to the pathogenesis and pathological processes of neurodegenerative diseases (NDs). Recently, optogenetics has now been applied to reveal the function of astrocytes in physiology and pathology. Herein, we discuss the possibility whether optogenetics could be used to control the release of gliotransmitters and regulate astrocytic membrane channels. Thus, the capability of modulating the bidirectional interactions between astrocytes and neurons in both synaptic and neuronal networks via optogenetics is evaluated. Furthermore, we discuss that manipulating astrocytes via optogenetics might be an effective way to investigate the potential therapeutic strategy for NDs.

Electrospun nanofibers of polyelectrolyte-surfactant complexes for antibacterial wound dressing application.

The development of polyelectrolyte-surfactant complexes (PESCs) has attracted extensive research interest in different fields of applications. However, the liquid state of PESCs has limited their utility in applications where solid materials are required. In this study, novel antibacterial fibers were fabricated via electrospinning PESCs in the solid state without any additives. The PESCs were prepared in aqueous mixtures of pre-hydrolyzed polyacrylonitrile (HPAN), a polyelectrolyte, and cetyltrimethyl ammonium chloride (CTAC), an antibacterial cationic surfactant, by taking advantage of the self-aggregation behavior of the polyelectrolyte and surfactant, which increased the antibacterial agent loading ability and, thus, the antibacterial activity of polymers. By release-killing and contact-killing mechanisms, the as-spun PESC nanofibrous membranes exhibited strong antibacterial ability against both Gram-positive and Gram-negative bacteria, killing 5 log CFU of E. coli and S. aureus within a contact time as short as 30 min. Furthermore, PESCs were blended with polycaprolactone (PCL) to prepare composite nanofibrous membranes as a novel wound dressing, which showed excellent antibacterial activity and favorable cytocompatibility, with the mechanical strength high enough to satisfy the clinical application requirements. The PESC fibers with durable antibacterial activity presented in the current work would be promising for medical applications.

Chronological Lifespan in Yeast Is Dependent on the Accumulation of Storage Carbohydrates Mediated by Yak1, Mck1 and Rim15 Kinases.

Upon starvation for glucose or any other macronutrient, yeast cells exit from the mitotic cell cycle and acquire a set of characteristics that are specific to quiescent cells to ensure longevity. Little is known about the molecular determinants that orchestrate quiescence entry and lifespan extension. Using starvation-specific gene reporters, we screened a subset of the yeast deletion library representing the genes encoding 'signaling' proteins. Apart from the previously characterised Rim15, Mck1 and Yak1 kinases, the SNF1/AMPK complex, the cell wall integrity pathway and a number of cell cycle regulators were shown to be necessary for proper quiescence establishment and for extension of chronological lifespan (CLS), suggesting that entry into quiescence requires the integration of starvation signals transmitted via multiple signaling pathways. The CLS of these signaling mutants, and those of the single, double and triple mutants of RIM15, YAK1 and MCK1 correlates well with the amount of storage carbohydrates but poorly with transition-phase cell cycle status. Combined removal of the glycogen and trehalose biosynthetic genes, especially GSY2 and TPS1, nearly abolishes the accumulation of storage carbohydrates and severely reduces CLS. Concurrent overexpression of GSY2 and TSL1 or supplementation of trehalose to the growth medium ameliorates the severe CLS defects displayed by the signaling mutants (rim15Δyak1Δ or rim15Δmck1Δ). Furthermore, we reveal that the levels of intracellular reactive oxygen species are cooperatively controlled by Yak1, Rim15 and Mck1, and the three kinases mediate the TOR1-regulated accumulation of storage carbohydrates and CLS extension. Our data support the hypothesis that metabolic reprogramming to accumulate energy stores and the activation of anti-oxidant defence systems are coordinated by Yak1, Rim15 and Mck1 kinases to ensure quiescence entry and lifespan extension in yeast.

Manipulation of hippocampal CA3 firing via luminopsins modulates spatial and episodic short-term memory, especially working memory, but not long-term memory.

The CA3 subregion of the hippocampus is important for rapid encoding, storage and retrieval of associative memories. Lesions and pharmacological inhibitions of hippocampal CA3 suggest that it is essential for different memories. However, how CA3 functions in spatial and episodic memory in different time scales (i.e. short-term versus long term) without permanent lesions has not been systematically investigated yet. Taking advantage of the chemogenetic access to opsins, this study used luminopsins, fusion proteins of luciferase and optogenetic elements, to manipulate neuronal activity in CA3 during memory tasks over a range of spatial and temporal scales. In this study, we found that excitation or inhibition of CA3 neurons had no significant effects on long-term spatial or episodic memory, but had remarkable effects on spatial working memory, spatial short-term memory as well as episodic short-term memory. In addition, stimulation of CA3 neurons altered the expression levels of NR2A. Intracerebral injection of receptor inhibitors further confirmed that NR2A is crucial to spatial working memory, which is consistent with the luminopsins experiments. These findings indicate that CA3 maintains a specific role on spatial and episodic memory over a short period of time.

The Yeast GSK-3 Homologue Mck1 Is a Key Controller of Quiescence Entry and Chronological Lifespan.

Upon starvation for glucose or any other core nutrient, yeast cells exit from the mitotic cell cycle and acquire a set of G0-specific characteristics to ensure long-term survival. It is not well understood whether or how cell cycle progression is coordinated with the acquisition of different G0-related features during the transition to stationary phase (SP). Here, we identify the yeast GSK-3 homologue Mck1 as a key regulator of G0 entry and reveal that Mck1 acts in parallel to Rim15 to activate starvation-induced gene expression, the acquisition of stress resistance, the accumulation of storage carbohydrates, the ability of early SP cells to exit from quiescence, and their chronological lifespan. FACS and microscopy imaging analyses indicate that Mck1 promotes mother-daughter cell separation and together with Rim15, modulates cell size. This indicates that the two kinases coordinate the transition-phase cell cycle, cell size and the acquisition of different G0-specific features. Epistasis experiments place MCK1, like RIM15, downstream of RAS2 in antagonising cell growth and activating stress resistance and glycogen accumulation. Remarkably, in the ras2∆ cells, deletion of MCK1 and RIM15 together, compared to removal of either of them alone, compromises respiratory growth and enhances heat tolerance and glycogen accumulation. Our data indicate that the nutrient sensor Ras2 may prevent the acquisition of G0-specific features via at least two pathways. One involves the negative regulation of the effectors of G0 entry such as Mck1 and Rim15, while the other likely to involve its functions in promoting respiratory growth, a phenotype also contributed by Mck1 and Rim15.

Epigallocatechin Gallate (EGCG) Inhibits Alpha-Synuclein Aggregation: A Potential Agent for Parkinson's Disease.

Protein aggregation is a prominent feature of many neurodegenerative disorders including Parkinson's disease (PD). Aggregation of alpha-synuclein (SNCA) may underlie the pathology of PD. They are the main components of Lewy bodies and dystrophic neurites that are the intraneuronal inclusions characteristic of the disease. We have demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibited SNCA aggregation, which made it a candidate for therapeutic intervention in PD. Three methods were used: SNCA fibril formation inhibition by EGCG in incubates; inhibition of the SNCA fluorophore A-Syn-HiLyte488 binding to plated SNCA in microwells; and inhibition of the A-Syn-HiLyte488 probe binding to aggregated SNCA in postmortem PD tissue. Recombinant human SNCA was incubated under conditions that result in fibril formation. The aggregation was blocked by 100 nM EGCG in a concentration-dependent manner, as shown by an absence of thioflavin T binding. In the microplate assay system, the ED50 of EGCG inhibition of A-Syn-HiLyte488 binding to coated SNCA was 250 nM. In the PD tissue based assay, SNCA aggregates were recognized by incubation with 7 nM of A-Syn-HiLyte488. This binding was blocked by EGCG in a concentration dependent manner. The SNCA amino acid sites, which potentially interacted with EGCG, were detected on peptide membranes. It was implicated that EGCG binds to SNCA by instable hydrophobic interactions. In this study, we suggested that EGCG could be a potent remodeling agent of SNCA aggregates and a potential disease modifying drug for the treatment of PD and other α-synucleinopathies.

Neural Network Excitation/Inhibition: A Key to Empathy and Empathy Impairment.

Empathy is an ability to fully understand and feel the mental states of others. We emphasize that empathy is elicited by the transmission of pain, fear, and sensory information. In clinical studies, impaired empathy has been observed in most psychiatric conditions. However, the precise impairment mechanism of the network systems on the pathogenesis of empathy impairment in psychiatric disorders is still unclear. Multiple lines of evidence suggest that disturbances in the excitatory/inhibitory balance in neurologic disorders are key to empathetic impairment in psychiatric disorders. Therefore, we here describe the roles played by the anterior cingulate cortex- and medial prefrontal cortex-dependent neural circuits and their impairments in psychiatric disorders, including anxiety, depression, and autism. In addition, we review recent studies on the role of microglia in neural network excitation/inhibition imbalance, which contributes to a better understanding of the neural network excitation/inhibition imbalance and may open up innovative psychiatric therapies.

The decreased astrocyte-microglia interaction reflects the early characteristics of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease often associated with olfactory dysfunction. Aß is a typical AD hall marker, but Aß-induced molecular alterations in olfactory memory remain unclear. In this study, we used a 5xFAD mouse model to investigate Aß-induced olfactory changes. Results showed that 4-month-old 5xFAD have olfactory memory impairment accompanied by piriform cortex neuron activity decline and no sound or working memory impairment. In addition, synapse and glia functional alteration is consistent across different ages at the proteomic level. Microglia and astrocyte specific proteins showed strong interactions in the conserved co-expression network module. Moreover, this interaction declines only in mild cognitive impairment patients in human postmortem brain proteomic data. This suggests that astrocytes-microglia interaction may play a leading role in the early stage of Aß-induced olfactory memory impairment, and the decreasing of their synergy may accelerate the neurodegeneration.

The Regulatory Mechanism of Rab21 in Human Diseases.

Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essential for normal cellular activities such as cell signaling, division, and survival. Due to their vital and irreplaceable role in regulating intracellular vesicle transportation, accumulated researches have shown that the abnormalities of Rab proteins and their effectors are closely related to human diseases. Here, this review focused on Rab21, a member of the Rab family, and introduced the structures and functions of Rab21, as well as the regulatory mechanisms of Rab21 in human diseases, including neurodegenerative diseases, cancer, and inflammation. In summary, we described in detail the role of Rab21 in human diseases and provide insights into the potential of Rab21 as a therapeutic target for diseases.

The many faces of the zinc finger protein 335 in brain development and immune system.

Zinc finger protein 335 (ZNF335) plays a crucial role in the methylation and, consequently, regulates the expression of a specific set of genes. Variants of the ZNF335 gene have been identified as risk factors for microcephaly in a variety of populations worldwide. Meanwhile, ZNF335 has also been identified as an essential regulator of T-cell development. However, an in-depth understanding of the role of ZNF335 in brain development and T cell maturation is still lacking. In this review, we summarize current knowledge of the molecular mechanisms underlying the involvement of ZNF335 in neuronal and T cell development across a wide range of pre-clinical, post-mortem, ex vivo, in vivo, and clinical studies. We also review the current limitations regarding the study of the pathophysiological functions of ZNF335. Finally, we hypothesize a potential role for ZNF335 in brain disorders and discuss the rationale of targeting ZNF335 as a therapeutic strategy for preventing brain disorders.

Reward prediction error in learning-related behaviors.

Learning is a complex process, during which our opinions and decisions are easily changed due to unexpected information. But the neural mechanism underlying revision and correction during the learning process remains unclear. For decades, prediction error has been regarded as the core of changes to perception in learning, even driving the learning progress. In this article, we reviewed the concept of reward prediction error, and the encoding mechanism of dopaminergic neurons and the related neural circuities. We also discussed the relationship between reward prediction error and learning-related behaviors, including reversal learning. We then demonstrated the evidence of reward prediction error signals in several neurological diseases, including Parkinson's disease and addiction. These observations may help to better understand the regulatory mechanism of reward prediction error in learning-related behaviors.

Neuronal Circuits Associated with Fear Memory: Potential Therapeutic Targets for Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that is associated with long-lasting memories of traumatic experiences. Extinction and discrimination of fear memory have become therapeutic targets for PTSD. Newly developed optogenetics and advanced in vivo imaging techniques have provided unprecedented spatiotemporal tools to characterize the activity, connectivity, and functionality of specific cell types in complicated neuronal circuits. The use of such tools has offered mechanistic insights into the exquisite organization of the circuitry underlying the extinction and discrimination of fear memory. This review focuses on the acquisition of more detailed, comprehensive, and integrated neural circuits to understand how the brain regulates the extinction and discrimination of fear memory. A future challenge is to translate these researches into effective therapeutic treatment for PTSD from the perspective of precise regulation of the neural circuits associated with the extinction and discrimination of fear memories.

In silico identification of novel stilbenes analogs for potential multi-targeted drugs against Alzheimer's disease.

CONTEXT: Alzheimer's disease (AD) is a chronic progressive neurodegenerative syndrome, which adversely disturbs cognitive abilities as well as intellectual processes and frequently occurs in the elderly. Inhibition of cholinesterase is a valuable approach to upsurge acetylcholine concentrations in the brain and persuades the development of multi-targeted ligands against cholinesterases. METHODS: The current study aims to determine the binding potential accompanied by antioxidant and anti-inflammatory activities of stilbenes-designed analogs against both cholinesterases (Acetylcholinesterase and butyrylcholinesterase) and neurotrophin targets for effective AD therapeutics. Docking results have shown that the WS6 compound exhibited the least binding energy - 10.1 kcal/mol with Acetylcholinesterase and - 7.8 kcal/mol with butyrylcholinesterase. The WS6 also showed a better binding potential with neurotrophin targets that are Brain-derived Neurotrophic Factor, Neurotrophin 4, Nerve Growth Factor, and Neurotrophin 3. The tested compounds particularly WS6 revealed significant antioxidant and anti-inflammatory activities through the comparative docking analysis with Fluorouracil and Melatonin as control drugs of antioxidants while Celecoxib and Anakinra as anti-inflammatory. The bioinformatics approaches including molecular docking calculations followed by the pharmacokinetics analysis and molecular dynamic simulations were accomplished to explore the capabilities of designed stilbenes as effective and potential leads. Root mean square deviation, root mean square fluctuations, and MM-GBSA calculations were performed through molecular dynamic simulations to extract the structural and residual variations and binding free energies through the 50-ns time scale.

Clusterin is a Potential Therapeutic Target in Alzheimer's Disease.

In recent years, Clusterin, a glycosylated protein with multiple biological functions, has attracted extensive research attention. It is closely associated with the physiological and pathological states within the organism. Particularly in Alzheimer's disease (AD) research, Clusterin plays a significant role in the disease's occurrence and progression. Numerous studies have demonstrated a close association between Clusterin and AD. Firstly, the expression level of Clusterin in the brain tissue of AD patients is closely related to pathological progression. Secondly, Clusterin is involved in the deposition and formation of ß-amyloid, which is a crucial process in AD development. Furthermore, Clusterin may affect the pathogenesis of AD through mechanisms such as regulating inflammation, controlling cell apoptosis, and clearing pathological proteins. Therefore, further research on the relationship between Clusterin and AD will contribute to a deeper understanding of the etiology of this neurodegenerative disease and provide a theoretical basis for developing early diagnostic and therapeutic strategies for AD. This also makes Clusterin one of the research focuses as a potential biomarker for AD diagnosis and treatment monitoring.