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.

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.

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.

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.

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.

Mediodorsal thalamus-projecting anterior cingulate cortex neurons modulate helping behavior in mice.

Many species living in groups can perform prosocial behaviors via voluntarily helping others with or without benefits for themselves. To provide a better understanding of the neural basis of such prosocial behaviors, we adapted a preference lever-switching task in which mice can prevent harm to others by switching from using a lever that causes shocks to a conspecific one that does not. We found the harm avoidance behavior was mediated by self-experience and visual and social contact but not by gender or familiarity. By combining single-unit recordings and analysis of neural trajectory decoding, we demonstrated the dynamics of anterior cingulate cortex (ACC) neural activity changes synchronously with the harm avoidance performance of mice. In addition, ACC neurons projected to the mediodorsal thalamus (MDL) to modulate the harm avoidance behavior. Optogenetic activation of the ACC-MDL circuit during non-preferred lever pressing (nPLP) and inhibition of this circuit during preferred lever pressing (PLP) both resulted in the loss of harm avoidance ability. This study revealed the ACC-MDL circuit modulates prosocial behavior to avoid harm to conspecifics and may shed light on the treatment of neuropsychiatric disorders with dysfunction of prosocial behavior.

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.

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.

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.

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.

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.

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.

ACx-projecting cholinergic neurons in the NB influence the BLA ensembles to modulate the discrimination of auditory fear memory.

Animals need discriminating auditory fear memory (DAFM) to survive, but the related neural circuits of DAFM remain largely unknown. Our study shows that DAFM depends on acetylcholine (ACh) signal in the auditory cortex (ACx), which is projected from the nucleus basalis (NB). At the encoding stage, optogenetic inhibition of cholinergic projections of NB-ACx obfuscates distinct tone-responsive neurons of ACx recognizing from fear-paired tone to fear-unpaired tone signals, while simultaneously regulating the neuronal activity and reactivation of basal lateral amygdala (BLA) engram cells at the retrieval stage. This NBACh-ACx-BLA neural circuit for the modulation of DAFM is especially dependent on the nicotinic ACh receptor (nAChR). A nAChR antagonist reduces DAFM and diminishes the increased magnitude of ACx tone-responsive neuronal activity during the encoding stage. Our data suggest a critical role of NBACh-ACx-BLA neural circuit in DAFM: manipulation of the NB cholinergic projection to the ACx via nAChR during the encoding stage affects the activation of ACx tone-responsive neuron clusters and the BLA engram cells during the retrieval stage, thus modulating the DAFM.

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.

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.

Application and prospects of high-throughput screening for in vitro neurogenesis.

Over the past few decades, high-throughput screening (HTS) has made great contributions to new drug discovery. HTS technology is equipped with higher throughput, minimized platforms, more automated and computerized operating systems, more efficient and sensitive detection devices, and rapid data processing systems. At the same time, in vitro neurogenesis is gradually becoming important in establishing models to investigate the mechanisms of neural disease or deve lopmental processes. However, challenges remain in generating more mature and functional neurons with specific subtypes and in establishing robust and standardized three-dimensional (3D) in vitro models with neural cells cultured in 3D matrices or organoids representing specific brain regions. Here, we review the applications of HTS technologies on in vitro neurogenesis, especially aiming at identifying the essential genes, chemical small molecules and adaptive microenvironments that hold great prospects for generating functional neurons or more reproductive and homogeneous 3D organoids. We also discuss the developmental tendency of HTS technology, e.g., so-called next-generation screening, which utilizes 3D organoid-based screening combined with microfluidic devices to narrow the gap between in vitro models and in vivo situations both physiologically and pathologically.

Screening of Human Circular RNAs as Biomarkers for Early Onset Detection of Alzheimer's Disease.

Circular RNAs (circRNAs) are a distinctive type of endogenous non-coding RNAs, and their regulatory roles in neurological disorders have received immense attention. CircRNAs significantly contribute to the regulation of gene expression and progression of neurodegenerative disorders including Alzheimer's disease (AD). The current study aimed to identify circRNAs as prognostic and potential biomarkers in AD. The differentially expressed circRNAs among subjective cognitive decline, amnestic mild cognitive impairment, and age-matched normal donors were determined through Arraystar Human circRNA Array V2 analysis. The annotations of circRNAs-microRNA interactions were predicted by employing Arraystar's homemade microRNAs (miRNA) target prediction tool. Bioinformatics analyses comprising gene ontology enrichment, KEGG pathway, and network analysis were conducted. Microarray analysis revealed the 33 upregulated and 11 downregulated differentially expressed circRNAs (FC ≥ 1.5 and p-values ≤ 0.05). The top 10 differentially expressed upregulated and downregulated circRNAs have been chosen for further expression validation through quantitative real-time PCR and subsequently, hsa-circRNA_001481 and hsa_circRNA_000479 were confirmed experimentally. Bioinformatics analyses determined the circRNA-miRNA-mRNA interactions and microRNA response elements to inhibit the expression of miRNAs and mRNA targets. Gene ontology enrichment and KEGG pathways analysis revealed the functional clustering of target mRNAs suggesting the functional verification of these two promising circRNAs. It is concluded that human circRNA_001481 and circRNA_000479 could be utilized as potential biomarkers for the early onset detection of AD and the development of effective therapeutics.

Mitochondria and Other Organelles in Neural Development and Their Potential as Therapeutic Targets in Neurodegenerative Diseases.

The contribution of organelles to neural development has received increasing attention. Studies have shown that organelles such as mitochondria, endoplasmic reticulum (ER), lysosomes, and endosomes play important roles in neurogenesis. Specifically, metabolic switching, reactive oxygen species production, mitochondrial dynamics, mitophagy, mitochondria-mediated apoptosis, and the interaction between mitochondria and the ER all have roles in neurogenesis. Lysosomes and endosomes can regulate neurite growth and extension. Moreover, metabolic reprogramming represents a novel strategy for generating functional neurons. Accordingly, the exploration and application of mechanisms underlying metabolic reprogramming will be beneficial for neural conversion and regenerative medicine. There is adequate evidence implicating the dysfunction of cellular organelles-especially mitochondria-in neurodegenerative disorders, and that improvement of mitochondrial function may reverse the progression of these diseases through the reinforcement of adult neurogenesis. Therefore, these organelles have potential as therapeutic targets for the treatment of neurodegenerative diseases. In this review, we discuss the function of these organelles, especially mitochondria, in neural development, focusing on their potential as therapeutic targets in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

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.

Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy.

The mechanisms of the transplantation of neural stem cells (NSCs) in the treatment of Alzheimer's disease remain poorly understood. In this study, NSCs were transplanted into the hippocampal CA1 region of the rTg (tau P301L) 4510 mouse model, a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer's disease. The results revealed that NSC transplantation reduced the abnormal aggregation of tau, resulting in significant improvements in the short-term memory of the tauopathy model mice. Compared with wild-type and phosphate-buffered saline (PBS)-treated mice, mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue, particularly those related to the regulation of tau aggregation or misfolding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation, neurogenesis, and other neurobiological processes. Changes in the expression levels of key proteins were verified by western blot assays. These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer's disease treatment. This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology (approval No. SYXK-BIT-school of life science-2017-M03) in 2017.