Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist ß-amyloid peptides (Aß) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Comprehensive assessment of fine motor movement and cognitive function among older adults in China: a cross-sectional study.

BACKGROUND: Fine motor skills are closely related to cognitive function. However, there is currently no comprehensive assessment of fine motor movement and how it corresponds with cognitive function. To conduct a complete assessment of fine motor and clarify the relationship between various dimensions of fine motor and cognitive function. METHODS: We conducted a cross-sectional study with 267 community-based participants aged ≥ 60 years in Beijing, China. We assessed four tests performance and gathered detailed fine motor indicators using Micro-Electro-Mechanical System (MEMS) motion capture technology. The wearable MEMS device provided us with precise fine motion metrics, while Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. We adopted logistic regression to analyze the relationship between fine motor movement and cognitive function. RESULTS: 129 (48.3%) of the participants had cognitive impairment. The vast majority of fine motor movements have independent linear correlations with MoCA-BJ scores. According to logistic regression analysis, completion time in the Same-pattern tapping test (OR = 1.033, 95%CI = 1.003-1.063), Completion time of non-dominant hand in the Pieces flipping test (OR = 1.006, 95%CI = 1.000-1.011), and trajectory distance of dominant hand in the Pegboard test (OR = 1.044, 95%CI = 1.010-1.068), which represents dexterity, are related to cognitive impairment. Coordination, represented by lag time between hands in the Same-pattern tapping (OR = 1.663, 95%CI = 1.131-2.444), is correlated with cognitive impairment. Coverage in the Dual-hand drawing test as an important indicator of stability is negatively correlated with cognitive function (OR = 0.709, 95%CI = 0.6501-0.959). Based on the above 5-feature model showed consistently high accuracy and sensitivity at the MoCA-BJ score (ACU = 0.80-0.87). CONCLUSIONS: The results of a comprehensive fine-motor assessment that integrates dexterity, coordination, and stability are closely related to cognitive functioning. Fine motor movement has the potential to be a reliable predictor of cognitive impairment.

Ephrin B3 exacerbates colitis and colitis-associated colorectal cancer.

Ephrin B3, a member of Eph/ephrin family, contributes to embryogenesis and carcinogenesis, but few studies have suggested whether this ligand has regulatory effect on colitis. This study was to determine whether ephrin B3 played a role in colitis and colonic carcinogenesis. Dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated carcinogenesis model was established in Efnb3-deficient (Efnb3-/-) mice. Label-free quantitative proteomics were performed to identify the Efnb3-regulated proteins. Our results showed that Efnb3 knock out reduced the symptoms of DSS-induced colitis, such as disease activity index (DAI), inflammatory factors release, and dysfunction of the intestinal barrier. Quantitative proteomics revealed that Efnb3 regulated 95 proteins which clustered in the platelet degranulation, response to elevated platelet cytosolic Ca2+, MAPK signaling for integrins such as ITGB4. Furthermore, ephrin B3 inactived ITGB4/AKT signal pathway and then promoted epithelial barrier dysfunction. Simultaneously, ephrin B3 promoted Gremlin-1/NF-κB signal pathway and thereby increased inflammatory factors release. In addition, the higher level of Efnb3 in colon cancer patients is correlated with worse survival. Efnb3-/- mice exhibited susceptibility to AOM/DSS-induced colorectal cancer. Our finding discovered that Efnb3 played an important role in the development of colitis and colitis-associated colorectal cancer. Efnb3 deficiency improved the intestinal barrier by ITGB4 and suppressed inflammation via Gremlin-1/NF-κB signal pathway, which may provide a novel therapeutic strategy for the treatment of colitis and colitis-associated colorectal cancer.

ANGPTL2 binds MAG to efficiently enhance oligodendrocyte differentiation.

BACKGROUND: Oligodendrocytes have robust regenerative ability and are key players in remyelination during physiological and pathophysiological states. However, the mechanisms of brain microenvironmental cue in regulation of the differentiation of oligodendrocytes still needs to be further investigated. RESULTS: We demonstrated that myelin-associated glycoprotein (MAG) was a novel receptor for angiopoietin-like protein 2 (ANGPTL2). The binding of ANGPTL2 to MAG efficiently promoted the differentiation of oligodendrocytes in vitro, as evaluated in an HCN cell line. Angptl2-null mice had a markedly impaired myelination capacity in the early stage of oligodendrocyte development. These mice had notably decreased remyelination capacities and enhanced motor disability in a cuprizone-induced demyelinating mouse model, which was similar to the Mag-null mice. The loss of remyelination ability in Angptl2-null/Mag-null mice was similar to the Angptl2-WT/Mag-null mice, which indicated that the ANGPTL2-mediated oligodendrocyte differentiation effect depended on the MAG receptor. ANGPTL2 bound MAG to enhance its phosphorylation level and recruit Fyn kinase, which increased Fyn phosphorylation levels, followed by the transactivation of myelin regulatory factor (MYRF). CONCLUSION: Our study demonstrated an unexpected cross-talk between the environmental protein (ANGPTL2) and its surface receptor (MAG) in the regulation of oligodendrocyte differentiation, which may benefit the treatment of many demyelination disorders, including multiple sclerosis.

EphB2-dependent prefrontal cortex activation promotes long-range social approach and partner responsiveness.

Social behavior starts with dynamic approach prior to the final consummation. The flexible processes ensure mutual feedback across social brains to transmit signals. However, how the brain responds to the initial social stimuli precisely to elicit timed behaviors remains elusive. Here, by using real-time calcium recording, we identify the abnormalities of EphB2 mutant with autism-associated Q858X mutation in processing long-range approach and accurate activity of prefrontal cortex (dmPFC). The EphB2-dependent dmPFC activation precedes the behavioral onset and is actively associated with subsequent social action with the partner. Furthermore, we find that partner dmPFC activity is responsive coordinately to the approaching WT mouse rather than Q858X mutant mouse, and the social defects caused by the mutation are rescued by synchro-optogenetic activation in dmPFC of paired social partners. These results thus reveal that EphB2 sustains neuronal activation in the dmPFC that is essential for the proactive modulation of social approach to initial social interaction.

Effect of Entresto on Clinical Symptoms, Ventricular Remodeling, Rehabilitation, and Hospitalization Rate in Patients with Both Acute Myocardial Infarction and Acute Heart Failure.

Objective: To determine the influence of Entresto on clinical symptoms, ventricular remodeling (VR), and economic stress of patients with both acute myocardial infarction (AMI) and acute heart failure (AHF). Methods: Totally 120 patients with AMI complicated with AHF admitted to our hospital between January 2017 and August 2019 were enrolled and randomly assigned to an observation group (obs group) and a control group (con group) (each n = 60). The obs group was treated with Entresto, while the other with angiotensin-converting enzyme inhibitors (ACEI). After treatment, the efficacy on both groups was evaluated, and their cardiac function-associated indexes (left ventricular end-systolic diameter (LVESd), left ventricular end-diastolic dimension (LVEDd), left ventricular ejection fraction (LVEF), VR-associated indexes (interventricular septal thickness (IVST), and left ventricular mass index (LVMI)) were determined and compared before treatment and after 1 month of treatment. Additionally, their NT-pro-BNP, CRP, and TNF-α were tested and compared before and after treatment, and they were also compared in hospitalization time, treatment expense, readmission rate within one year after discharge, and adverse events. Results: After treatment, the obs group showed notably higher efficacy than the con group (P < 0.05). Before treatment, the two groups were not greatly different in LVESd, LVEDd, LVEF, IVST, LVMI, NT-pro BNP, CRP, and TNF-α (all P > 0.05), while after treatment, these indexes of both groups were improved, but the improvement in the obs group was more notable (P < 0.05). Additionally, the hospitalization time, treatment expense, readmission rate one year after discharge, and incidence of adverse events in the obs group were notably lower (all P < 0.05). Conclusion: For patients with both AMI and AHF, Entresto can contribute to strong amelioration of their clinical symptoms and prognosis and ventricular reverse-remodeling, with a high safety, so it is worthy of clinical promotion.

Scaffold Protein Lnx1 Stabilizes EphB Receptor Kinases for Synaptogenesis.

Postsynaptic structure assembly and remodeling are crucial for functional synapse formation during the establishment of neural circuits. However, how the specific scaffold proteins regulate this process during the development of the postnatal period is poorly understood. In this study, we find that the deficiency of ligand of Numb protein X 1 (Lnx1) leads to abnormal development of dendritic spines to impair functional synaptic formation. We further demonstrate that loss of Lnx1 promotes the internalization of EphB receptors from the cell surface. Constitutively active EphB2 intracellular signaling rescues synaptogenesis in Lnx1 mutant mice. Our data thus reveal a molecular mechanism whereby the Lnx1-EphB complex controls postsynaptic structure for synapse maturation during the adolescent period.

Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice.

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

Activation of spinal ephrin-B3/EphBs signaling induces hyperalgesia through a PLP-mediated mechanism.

Ephrin B/EphB signaling pathway is involved in the regulation of pain caused by spinal cord injury. However, the role of ephrin-B3/EphBs signaling in regulation of nociceptive information is poorly understood. In the present study, formalin-induced inflammatory pain, mechanical allodynia and thermal hyperalgesia, was measured using Efnb3 mutant mice (Efnb3-/- ) and wild-type (Efnb3+/+ ) mice. The spinal cord (L4-6) was selected for molecular and cellular identification by western blotting and immunofluorescence. Efnb3 mutant mice showed a significant increased the thermal and mechanical threshold, followed by aberrant thin myelin sheath. Furthermore, expression of proteolipid protein (PLP) was significantly lower in L4-6 spinal cord of Efnb3-/- mice. These morphological and behavioral abnormalities in mutant mice were rescued by conditional knock-in of wild-type ephrin-B3. Intrathecal administration of specific PLP siRNA significantly increased the thermal and mechanical threshold hyperalgesia in wild-type mice. However, overexpressing PLP protein by AAV9-PLP could decrease the sensitivity of mice to thermal and mechanical stimuli in Efnb3-/- mice, compared with scrabble Efnb3-/- mice. Further, Efnb3lacz mice, which have activities to initiate forward signaling, but transduce reverse signals by ephrin-B3, shows normal acute pain behavior, compared with wild type mice. These findings indicate that a key molecule Efnb3 act as a prominent contributor to hyperalgesia and essential roles of ephrin-B3/EphBs in nociception through a myelin-mediated mechanism.

Microfluidic Fabrication of Hierarchical-Ordered ZIF-L(Zn)@Ti3 C2 Tx Core-Sheath Fibers for High-Performance Asymmetric Supercapacitors.

We report hierarchical-ordered ZIF-L(Zn)@Ti3 C2 Tx MXene core-sheath fibers, in which a ZIF-L(Zn) nanowall array sheath is grown vertically on an anisotropic Ti3 C2 Tx core by Ti-O-Zn/Ti-F-Zn chemical bonds. Through highly efficient microfluidic assembly and microchannel reactions, ZIF-L(Zn)@Ti3 C2 Tx exhibits well-developed micro-/mesoporosity, ordered ionic pathways, fast interfacial electron conduction and large-scale fabrication, significantly boosting charges dynamic transport and intercalation. The resultant ZIF-L(Zn)@Ti3 C2 Tx fiber presents large capacitance (1700 F cm-3 ) and outstanding rate performance in a 1 M H2 SO4 electrolyte. Additionally, ZIF-L(Zn)@Ti3 C2 Tx fiber-based solid-state asymmetric supercapacitors deliver high energy density (19.0 mWh cm-3 ), excellent capacitance (854 F cm-3 ), large deformable/wearable capabilities and long-time cyclic stability (20 000 cycles), which realize natural sunlight-induced self-powered applications to drive water level/earthquake alarm devices.

Hippocampal Lnx1-NMDAR multiprotein complex mediates initial social memory.

Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1-NMDAR-EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1-/- mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.

Targeting neuroplasticity in patients with neurodegenerative diseases using brain stimulation techniques.

Deficits in synaptic transmission and plasticity are thought to contribute to the pathophysiology of Alzheimer's disease (AD) and Parkinson's disease (PD). Several brain stimulation techniques are currently available to assess or modulate human neuroplasticity, which could offer clinically useful interventions as well as quantitative diagnostic and prognostic biomarkers. In this review, we discuss several brain stimulation techniques, with a special emphasis on transcranial magnetic stimulation and deep brain stimulation (DBS), and review the results of clinical studies that applied these techniques to examine or modulate impaired neuroplasticity at the local and network levels in patients with AD or PD. The impaired neuroplasticity can be detected in patients at the earlier and later stages of both neurodegenerative diseases. However, current brain stimulation techniques, with a notable exception of DBS for PD treatment, cannot serve as adequate clinical tools to assist in the diagnosis, treatment, or prognosis of individual patients with AD or PD. Targeting the impaired neuroplasticity with improved brain stimulation techniques could offer a powerful novel approach for the treatment of AD and PD.

EphB2 mediates social isolation-induced memory forgetting.

Social isolation in adolescence leads to lasting deficits, including emotional and cognitive dysregulation. It remains unclear, however, how social isolation affects certain processes of memory and what molecular mechanisms are involved. In this study, we found that social isolation during the post-weaning period resulted in forgetting of the long-term fear memory, which was attributable to the downregulation of synaptic function in the hippocampal CA1 region mediated by EphB2, a receptor tyrosine kinase which involves in the glutamate receptor multiprotein complex. Viral-mediated EphB2 knockdown in CA1 mimicked the memory defects in group-housed mice, whereas restoration of EphB2 by either viral overexpression or resocialization reversed the memory decline in isolated mice. Taken together, our finding indicates that social isolation gives rise to memory forgetting by disrupting EphB2-mediated synaptic plasticity, which may provide a potential target for preventing memory loss caused by social isolation or loneliness.

Paroxetine ameliorates prodromal emotional dysfunction and late-onset memory deficit in Alzheimer's disease mice.

BACKGROUND: Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy, and irritability occur in prodromal phases of clinical Alzheimer's disease (AD), which might be an increased risk for later developing AD. Here we treated young APP/PS1 AD model mice prophylactically with serotonin-selective re-uptake inhibitor (SSRI) paroxetine and investigated the protective role of anti-depressant agent in emotional abnormalities and cognitive defects during disease progress. METHODS: To investigate the protective role of paroxetine in emotional abnormalities and cognitive defects during disease progress, we performed emotional behaviors of 3 months old APP/PS1 mouse following oral administration of paroxetine prophylactically starting at 1 month of age. Next, we tested the cognitive, biochemical and pathological, effects of long term administration of paroxetine at 6 months old. RESULTS: Our results showed that AD mice displayed emotional dysfunction in the early stage. Prophylactic administration of paroxetine ameliorated the initial emotional abnormalities and preserved the eventual memory function in AD mice. CONCLUSION: Our data indicate that prophylactic administration of paroxetine ameliorates the emotional dysfunction and memory deficit in AD mice. These neuroprotective effects are attributable to functional restoration of glutamate receptor (GluN2A) in AD mice.

Neuroprotective Effects of Salidroside in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by pathological hallmarks like ß-amyloid peptide (Aß) and clinical manifestations including cognitive impairment, psychiatry disorders, and behavioral changes. Salidroside (Sal) extracted from Rhodiola rosea L. showed protective effects against Aß-induced neurotoxicity in a Drosophila AD model in our previous research. In the present study, daily doses of Sal were administered to APP/PS1 mice, a mouse model of AD, and several parameters were tested, including behavioral performance, Aß status, levels of synapse-related proteins, and levels of PI3K/Akt targets of mTOR cell signaling pathway proteins. The behavioral testing showed an improvement in locomotor activity in the APP/PS1 mice after the administration of Sal. Treatment with Sal decreased both the soluble and insoluble Aß levels and increased the expression of PSD95, NMDAR1, and calmodulin-dependent protein kinase II. The phosphatidylinositide PI3K/Akt/mTOR signaling was upregulated, which was in accordance with the above improvements from Sal treatment. Our findings suggested that Sal may protect the damaged synapses of the neurons in the APP/PS1 mice.

Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy.

BACKGROUND: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. METHODS: In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. RESULTS: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24-46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. CONCLUSIONS: Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. TRIAL REGISTRATION: ChiCTR, ChiCTR1800015295. Registered 21 March 2018.

The activated newborn neurons participate in enriched environment induced improvement of locomotor function in APP/PS1 mice.

INTRODUCTION: Alzheimer's disease (AD) is an age-related neurodegenerative disorder. One of the pathological features of AD is neuronal loss in brain regions associated with cognition, particularly the hippocampus. An enriched environment (EE) can facilitate neuronal plasticity and improve behaviors such as emotion, motor function, and cognition in AD. METHODS: After APP/PS1 mice were exposed to EE at an early stage (2 months of age), elevated plus maze performance and contextual fear conditioning were tested, and neurogenesis and the extent of activation in the hippocampus were observed. RESULTS: The results showed that, compared with that in the mice that experienced a standard environment, the cognition of the mice exposed to EE, as measured by contextual fear conditioning, was not statistically significant. However, based on their performance in the elevated plus maze, the index was increased in the mice, especially the APP/PS1 mice, exposed to EE. Consistent with the behavioral changes, the APP/PS1 mice exposed to EE showed an increased number of c-Fos-positive neurons and elevated neurogenesis in the dentate gyrus (DG) area. In addition, the activation of newborn neurons did not occur in the other three groups. CONCLUSIONS: These results indicate that the activation of newborn neurons may participate in the improvement of behavioral performance in APP/PS1 mice after EE.