Grainyhead-like 2 interacts with noggin to regulate tissue fusion in mouse.

Defective tissue fusion during mammalian embryogenesis results in congenital anomalies, such as exencephaly, spina bifida and cleft lip and/or palate. The highly conserved transcription factor grainyhead-like 2 (Grhl2) is a crucial regulator of tissue fusion, with mouse models lacking GRHL2 function presenting with a fully penetrant open cranial neural tube, facial and abdominal clefting (abdominoschisis), and an open posterior neuropore. Here, we show that GRHL2 interacts with the soluble morphogen protein and bone morphogenetic protein (BMP) inhibitor noggin (NOG) to impact tissue fusion during development. The maxillary prominence epithelium in embryos lacking Grhl2 shows substantial morphological abnormalities and significant upregulation of NOG expression, together with aberrantly distributed pSMAD5-positive cells within the neural crest cell-derived maxillary prominence mesenchyme, indicative of disrupted BMP signalling. Reducing this elevated NOG expression (by generating Grhl2-/-;Nog+/- embryos) results in delayed embryonic lethality, partial tissue fusion rescue, and restoration of tissue form within the craniofacial epithelia. These data suggest that aberrant epithelial maintenance, partially regulated by noggin-mediated regulation of BMP-SMAD pathways, may underpin tissue fusion defects in Grhl2-/- mice.

PD-1 deficiency aggravates spinal cord injury by regulating the reprogramming of NG2 glia and activating the NgR/RhoA/ROCK signaling pathway.

Spinal cord injury (SCI) is a devastating disorder and a leading cause of disability in adults worldwide. Multiple studies have reported the upregulation of programmed cell death 1 (PD-1) following SCI. However, the underlying mechanism of PD-1 deficiency in SCI is not well established. Therefore, we aimed to investigate the role and potential mechanism of PD-1 in SCI pathogenesis. PD-1 Knockout (KO) SCI mouse model was established, and PD-1 expression was evaluated in tissue samples by western blot assay. We then used a series of function gain-and-loss assays to determine the role of PD-1 in SCI pathogenesis. Moreover, mechanistic assays were performed to explore the association between PD-1, neuron-glia antigen-2 (NG2) glia cells, and miR-23b-5p and then investigated the involved signaling pathway. Results illustrated that PD-1 deficiency enhanced the inflammatory response, neuron loss, and functional impairment induced by SCI. We found that NG2 glia depletion aggravated inflammation, reduced neural survival, and suppressed locomotor recovery in murine SCI model. Further analysis indicated that NG2+ cells were increased in the spinal cord of SCI mice, and PD-1 deficiency increased the number of NG2+ cells by activating the Nogo receptor/ras homolog family member A/Rho kinase (NgR/RhoA/ROCK) signaling. Mechanistically, miR-23b-5p was identified as the negative regulator of PD-1 in NG2 glia. MiR-23b-5p deficiency reduced the expression of inflammatory cytokines, enhanced neural survival, and promoted locomotor recovery in SCI mice, which was counteracted by PD-1 deficiency. In conclusion, PD-1 deficiency exacerbates SCI in vivo by regulating reprogramming of NG2 glia and activating the NgR/RhoA/ROCK signaling.

Behavioral stress and antidepressant treatments altered hippocampal expression of Nogo signal-related proteins in rats.

Some immune molecules including neurite outgrowth inhibitor (Nogo) ligands and their receptor（Nogo receptor-1: NgR1）are expressed at the neuronal synaptic sites. Paired immunoglobulin-like receptor B (PirB) is another Nogo receptor that also binds to major histocompatibility complex I and ß-amyloid and suppresses dendritic immune cell functions and neuronal plasticity in the central nervous system. Augmenting structural and functional neural plasticity by manipulating the Nogo signaling pathway is a novel promising strategy for treating brain ischemia and degenerative processes such as Alzheimer's disease. In recent decades psychiatric research using experimental animals has focused on the attenuation of neural plasticity by stress loadings and on the enhanced resilience by psychopharmacological treatments. In the present study, we examined possible expressional alterations in Nogo signal-related proteins in the rat hippocampus after behavioral stress loadings and antidepressant treatments. To validate the effectiveness of the procedures, previously reported increase in brain-derived neurotrophic factor (BDNF) by ECS or ketamine administration and decrease of BDNF by stress loadings are also shown in the present study. Significant increases in hippocampal NgR1 and PirB expression were observed following chronic variable stress, and a significant increase in NgR1 expression was observed under a single prolonged stress paradigm. These results indicate a possible contribution of enhanced Nogo signaling to the attenuation of neural plasticity in response to stressful experiences. Additionally, the suppression of hippocampal NgR1 expression using electroconvulsive seizure treatment and administration of subanesthetic dose of ketamine supported the increased neural plasticity induced by the antidepressant treatments.

Inhibition of the Nogo-pathway in experimental spinal cord injury: a meta-analysis of 76 experimental treatments.

Recovery after spinal cord injury (SCI) may be propagated by plasticity-enhancing treatments. The myelin-associated nerve outgrowth inhibitor Nogo-A (Reticulon 4, RTN4) pathway has been shown to restrict neuroaxonal plasticity in experimental SCI models. Early randomized controlled trials are underway to investigate the effect of Nogo-A/Nogo-Receptor (NgR1) pathway blockers. This systematic review and meta-analysis of therapeutic approaches blocking the Nogo-A pathway interrogated the efficacy of functional locomotor recovery after experimental SCI according to a pre-registered study protocol. A total of 51 manuscripts reporting 76 experiments in 1572 animals were identified for meta-analysis. Overall, a neurobehavioral improvement by 18.9% (95% CI 14.5-23.2) was observed. Subgroup analysis (40 experiments, N = 890) revealed SCI-modelling factors associated with outcome variability. Lack of reported randomization and smaller group sizes were associated with larger effect sizes. Delayed treatment start was associated with lower effect sizes. Trim and Fill assessment as well as Egger regression suggested the presence of publication bias. Factoring in theoretically missing studies resulted in a reduced effect size [8.8% (95% CI 2.6-14.9)]. The available data indicates that inhibition of the Nogo-A/NgR1pathway alters functional recovery after SCI in animal studies although substantial differences appear for the applied injury mechanisms and other study details. Mirroring other SCI interventions assessed earlier we identify similar factors associated with outcome heterogeneity.

Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial.

PURPOSE OF REVIEW: After traumatic spinal cord injury (SCI), neurological deficits persist due to the disconnection of surviving neurons. While repair of connectivity may restore function, no medical therapy exists today.This review traces the development of the neural repair-based therapeutic AXER-204 from animal studies to the recent clinical trial for chronic cervical SCI. RECENT FINDINGS: Molecular studies reveal a Nogo-66 Receptor 1 (NgR1, RTN4R) pathway inhibiting axon regeneration, sprouting, and plasticity in the adult mammalian central nervous system (CNS). Rodent and nonhuman primate studies demonstrate that the soluble receptor decoy NgR(310)ecto-Fc or AXER-204 promotes neural repair and functional recovery in transection and contusion SCI. Recently, this biological agent completed a first-in-human and randomized clinical trial for chronic cervical SCI. The intervention was safe and well tolerated. Across all participants, upper extremity strength did not improve with treatment. However, posthoc and biomarker analyses suggest that AXER-204 may benefit treatment-naïve patients with incomplete SCI in the chronic stage. SUMMARY: NgR1 signaling restricts neurological recovery in animal studies of CNS injury. The recent clinical trial of AXER-204 provides encouraging signals supporting future focused trials of this neural repair therapeutic. Further, AXER-204 studies provide a roadmap for the development of additional and synergistic therapies for chronic SCI.

Unveiling the modulation of Nogo receptor in neuroregeneration and plasticity: Novel aspects and future horizon in a new frontier.

Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Multiple Sclerosis, Hereditary Spastic Paraplegia, and Amyotrophic Lateral Sclerosis have emerged as the most dreaded diseases due to a lack of precise diagnostic tools and efficient therapies. Despite the fact that the contributing factors of NDs are still unidentified, mounting evidence indicates the possibility that genetic and cellular changes may lead to the significant production of abnormally misfolded proteins. These misfolded proteins lead to damaging effects thereby causing neurodegeneration. The association between Neurite outgrowth factor (Nogo) with neurological diseases and other peripheral diseases is coming into play. Three isoforms of Nogo have been identified Nogo-A, Nogo-B and Nogo-C. Among these, Nogo-A is mainly responsible for neurological diseases as it is localized in the CNS (Central Nervous System), whereas Nogo-B and Nogo-C are responsible for other diseases such as colitis, lung, intestinal injury, etc. Nogo-A, a membrane protein, had first been described as a CNS-specific inhibitor of axonal regeneration. Several recent studies have revealed the role of Nogo-A proteins and their receptors in modulating neurite outgrowth, branching, and precursor migration during nervous system development. It may also modulate or affect the inhibition of growth during the developmental processes of the CNS. Information about the effects of other ligands of Nogo protein on the CNS are yet to be discovered however several pieces of evidence have suggested that it may also influence the neuronal maturation of CNS and targeting Nogo-A could prove to be beneficial in several neurodegenerative diseases.

Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2.

Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. We provide evidence that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury.

[Fasudil reduces apoptosis of SH-SY5Y cells induced by H2O2 and promotes synaptic plasticity by inhibiting neurite outgrowth inhibitor A and its receptor (NogoA/NgR) signaling pathway].

Objective To investigate the effect of Fasudil on H2O2-induced apoptosis and synaptic plasticity in human neuroblastoma SY5Y cells and its mechanism. Methods The cells were divided into three groups: PBS control group, H2O2 model group (250 µmol/L H2O2 treatment) and Fasudil intervention group (250 µmol/L H2O2 combined with 15 µg/mL Fasudil treatment). MTT assay was applied to detect cell activity and TUNEL was performed to detect cell apoptosis respectively. Immunofluorescence cytochemical staining was used to determine the expression of neurite outgrowth inhibitor A (NogoA), Nogo receptor (NgR) and synaptophysin (Syn). Western blotting was then conducted to detect the expression of NogoA, NgR, p75 neurotrophin receptor (p75NTR), leucine-rich repeat Ig domain-containing Nogo-interacting protein 1 (LINGO-1), Syn and postsynaptic density protein-95 (PSD-95). Results Compared with the PBS group, the H2O2 group showed decreased cell viability and increased apoptosis rate while Fasudil treatment significantly increased the cell viability and reduced the apoptosis rate. Compared with the H2O2 model group, Fasudil intervention increased expressions of Syn and PSD-95. Compared with the PBS group, the expression of NogoA and its receptor complex NgR/p75NTR/LINGO-1 grew significantly in the H2O2 group, suggesting Fasudil treatment could inhibit the expression of NogoA and its receptor complex NgR/p75NTR/LINGO-1. Conclusion Fasudil may inhibit the activation of the NogoA/NgR signaling pathway, therefore reducing the apoptosis induced by H2O2 in SH-SY5Y cells and enhancing the plasticity of the synapses.

Shenfu Injection Protects Brain Injury in Rats with Cardiac Arrest through Nogo/NgR Pathway.

The effect of Shenfu injection on brain injury after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) along with the underlying mechanism of axonal regeneration was explored. CA/CPR model in rats was established for subsequent experiments. A total of 160 rats were randomly divided into sham group, model group, conventional western medicine (CWM) group, Shenfu group, and antagonist group (n = 32 per group). After 3 hours, 24 hours, 3 days, and 7 days of drug administration, the modified Neurological Severity Score tests were performed. The ultrastructure of the brain and hippocampus was observed by electron microscopy. Real-time quantitative polymerase chain reaction (PCR), western blotting, and immunohistochemistry were used to detect Nogo receptor (NgR) expression in the hippocampus and cerebral cortex, and Nogo-NgR expression in CA/CPR model. Neurological deficits in the model group were severe at 3 hours, 24 hours, 3 days, and 7 days after the recovery of natural circulation, whereas the neurological deficits in CWM, antagonist, and Shenfu group were relatively mild. The ultrastructure of neuronal cells in Shenfu group had relatively complete cell membranes and more vesicles than those in the model group. The results of PCR and western blotting showed lower messenger ribonucleic acid and protein expression of NgR in Shenfu group than the model group and CWM group. Immunohistochemical examination indicated a reduction of Nogo-NgR expression in Shenfu group and antagonist group. Our results suggested that Shenfu injection reduced brain injury by attenuating Nogo-NgR signaling pathway and promoting axonal regeneration.

RTN4/NoGo-receptor binding to BAI adhesion-GPCRs regulates neuronal development.

RTN4-binding proteins were widely studied as "NoGo" receptors, but their physiological interactors and roles remain elusive. Similarly, BAI adhesion-GPCRs were associated with numerous activities, but their ligands and functions remain unclear. Using unbiased approaches, we observed an unexpected convergence: RTN4 receptors are high-affinity ligands for BAI adhesion-GPCRs. A single thrombospondin type 1-repeat (TSR) domain of BAIs binds to the leucine-rich repeat domain of all three RTN4-receptor isoforms with nanomolar affinity. In the 1.65 Å crystal structure of the BAI1/RTN4-receptor complex, C-mannosylation of tryptophan and O-fucosylation of threonine in the BAI TSR-domains creates a RTN4-receptor/BAI interface shaped by unusual glycoconjugates that enables high-affinity interactions. In human neurons, RTN4 receptors regulate dendritic arborization, axonal elongation, and synapse formation by differential binding to glial versus neuronal BAIs, thereby controlling neural network activity. Thus, BAI binding to RTN4/NoGo receptors represents a receptor-ligand axis that, enabled by rare post-translational modifications, controls development of synaptic circuits.

Nogo receptor impairs the clearance of fibril amyloid-ß by microglia and accelerates Alzheimer's-like disease progression.

Alzheimer's disease (AD) is characterized by the progressive accumulation of ß-amyloid (Aß)-containing amyloid plaques, and microglia play a critical role in mediating Aß clearance. Mounting evidence has confirmed that the ability of microglia in clearing Aß decreased with aging and AD progress, but the underlying mechanisms are unclear. Previously, we have demonstrated that Nogo receptor (NgR), a receptor for three axon growth inhibitors associated with myelin, can decrease adhesion and migration of microglia to fibrils Aß with aging. However, whether NgR expressed on microglia affect microglia phagocytosis of fibrils Aß with aging remains unclear. Here, we found that aged but not young microglia showed increased NgR expression and decreased Aß phagocytosis in APP/PS1 transgenic mice. NgR knockdown APP/PS1 mice showed simultaneous reduced amyloid burden and improved spatial learning and memory, which were associated with increased Aß clearance. Importantly, Nogo-P4, an agonist of NgR, enhanced the protein level of p-Smad2/3, leading to a significant transcriptional inhibition of CD36 gene expression, which in turn decreased the microglial phagocytosis of Aß. Moreover, ROCK accounted for Nogo-P4-induced activation of Smad2/3 signaling. Finally, the decreasing effect of NgR on microglial Aß uptake was confirmed in a mouse model of intra-hippocampal fAß injection. Our findings suggest that NgR may play an important role in the regulation of Aß homeostasis, and has potential as a therapeutic target for AD.

Plasticity-Enhancing Effects of Levodopa Treatment after Stroke.

Dopaminergic treatment in combination with rehabilitative training enhances long-term recovery after stroke. However, the underlying mechanisms on structural plasticity are unknown. Here, we show an increased dopaminergic innervation of the ischemic territory during the first week after stroke induced in Wistar rats subjected to transient occlusion of the middle cerebral artery (tMCAO) for 120 min. This response was also found in rats subjected to permanent focal ischemia induced by photothrombosis (PT) and mice subjected to PT or tMCAO. Dopaminergic branches were detected in the infarct core of mice and rats in both stroke models. In addition, the Nogo A pathway was significantly downregulated in rats treated with levodopa (LD) compared to vehicle-treated animals subjected to tMCAO. Specifically, the number of Nogo A positive oligodendrocytes as well as the levels of Nogo A and the Nogo A receptor were significantly downregulated in the peri-infarct area of LD-treated animals, while the number of Oligodendrocyte transcription factor 2 positive cells increased in this region after treatment. In addition, we observed lower protein levels of Growth Associated Protein 43 in the peri-infarct area compared to sham-operated animals without treatment effect. The results provide the first evidence of the plasticity-promoting actions of dopaminergic treatment following stroke.

B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF.

We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1+/+ EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells of ngr1+/+ EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.

Anti-apoptotic efficacy of Qingnao Yizhi formula in hypoxia/reoxygenation primary cortical neurons through the promotion of synaptic plasticity by modulating the NogoA-Nogo receptor/Rho-Rho kinase signaling pathway.

OBJECTIVE: To evaluate the anti-apoptotic efficacy of Qingnao Yizhi formula (，QNYZ) in cultured cerebral cortical neuronal cells (CNCs) and the regulation of the NogoA-Nogo receptor (NgR)/Rho-Rho kinase (ROCK) signaling pathway. METHODS: Primary cultured CNCs were randomly divided into the following groups: normal control group (N-C), hypoxia-reoxygenation group (H/R), high-dose QNYZ group (Q-H), low-dose QNYZ group (Q-L) butylphthalide (NBP) group, and Y-27632 (a selective ROCK transduction pathway inhibiter) group. Except those in the N-C group, CNCs were placed in hypoxic conditions for 24 h and then in reoxygenation conditions for 24 h. Cell media was changed every 48 h, and various assays were performed on the 7th day. Cell viability was evaluated by measuring mitochondrial dehydrogenase activity, using a CCK-8 assay, in triplicate. Synapsin (SYN) protein concentrations were evaluated by enzyme-linked immunosorbent assay. NogoA and RhoA protein expression were evaluated through Western blotting. The gene expression of NogoA, NgR, RhoA, and ROCK was evaluated by reverse transcription-polymerase chain reaction. Cell apoptosis was measured using a terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay. RESULTS: Compared with the N-C group, the cell viability of the H/R group decreased significantly (P < 0.05). The cell viability values for the Q-H and Q-L groups increased compared with that for the H/R group, and the difference was significant for the Q-H group (P < 0.05). The NogoA and RhoA protein levels and the NogoA, NgR, RhoA, and ROCK mRNA expression levels increased in the H/R group, compared with the N-C group, and decreased significantly in the Q-H and Q-L groups (P < 0.05) and in the Y-27632 group (P < 0.05) compared with the H/R group. The SYN levels in the Q-H, Q-L, and NBP groups significantly increased compared with that in the H/R group (P < 0.05). Compared with the H/R group, the numbers of apoptotic cells in the Q-H, Q-L, and NBP groups significantly decreased (P < 0.05). CONCLUSION: The presented study demonstrated that QNYZ exerted anti-apoptotic effects on H/R-induced CNCs, possibly through the modulation of the NogoA-NgR/Rho-ROCK signaling pathway and the promotion of synaptic plasticity in H/R CNCs.

Constraint-Induced Movement Therapy Promotes Neural Remodeling and Functional Reorganization by Overcoming Nogo-A/NgR/RhoA/ROCK Signals in Hemiplegic Cerebral Palsy Mice.

Background. Little is known about the induction of functional and brain structural reorganization in hemiplegic cerebral palsy (HCP) by constraint-induced movement therapy (CIMT). Objective. We aimed to explore the specific molecular mechanism of functional and structural plasticity related to CIMT in HCP. Methods. The mice were divided into a control group and HCP groups with different interventions (unconstraint-induced movement therapy [UNCIMT], CIMT or siRNA-Nogo-A [SN] treatment): the HCP, HCP+UNCIMT, HCP+CIMT, HCP+SN, and HCP+SN+CIMT groups. Rotarod and front-limb suspension tests, immunohistochemistry, Golgi-Cox staining, transmission electron microscopy, and Western blot analyses were applied to measure motor function, neurons and neurofilament density, dendrites/axon areas, myelin integrity, and Nogo-A/NgR/RhoA/ROCK expression in the motor cortex. Results. The mice in the HCP+CIMT group had better motor function, greater neurons and neurofilament density, dendrites/axon areas, myelin integrity, and lower Nogo-A/NgR/RhoA/ROCK expression in the motor cortex than the HCP and HCP+UNCIMT groups (P < .05). Moreover, the expression of Nogo-A/NgR/RhoA/ROCK, the improvement of neural remodeling and motor function of mice in the HCP+SN group were similar to those in the HCP+CIMT group (P > .05). The neural remodeling and motor function of the HCP+SN+CIMT group were significantly greater than those in the HCP+SN and HCP+CIMT groups (P < .05). Motor function were positively correlated with the density of neurons (r = 0.450 and 0.309, respectively; P < .05) and neurofilament (r = 0.717 and 0.567, respectively; P < .05). Conclusions. CIMT might promote the remodeling of neurons, neurofilament, dendrites/axon areas, and myelin in the motor cortex by partially inhibiting the Nogo-A/NgR/RhoA/ROCK pathway, thereby promoting the improvement of motor function in HCP mice.

Single-nucleus RNA sequencing of mouse auditory cortex reveals critical period triggers and brakes.

Auditory experience drives neural circuit refinement during windows of heightened brain plasticity, but little is known about the genetic regulation of this developmental process. The primary auditory cortex (A1) of mice exhibits a critical period for thalamocortical connectivity between postnatal days P12 and P15, during which tone exposure alters the tonotopic topography of A1. We hypothesized that a coordinated, multicellular transcriptional program governs this window for patterning of the auditory cortex. To generate a robust multicellular map of gene expression, we performed droplet-based, single-nucleus RNA sequencing (snRNA-seq) of A1 across three developmental time points (P10, P15, and P20) spanning the tonotopic critical period. We also tone-reared mice (7 kHz pips) during the 3-d critical period and collected A1 at P15 and P20. We identified and profiled both neuronal (glutamatergic and GABAergic) and nonneuronal (oligodendrocytes, microglia, astrocytes, and endothelial) cell types. By comparing normal- and tone-reared mice, we found hundreds of genes across cell types showing altered expression as a result of sensory manipulation during the critical period. Functional voltage-sensitive dye imaging confirmed GABA circuit function determines critical period onset, while Nogo receptor signaling is required for its closure. We further uncovered previously unknown effects of developmental tone exposure on trajectories of gene expression in interneurons, as well as candidate genes that might execute tonotopic plasticity. Our single-nucleus transcriptomic resource of developing auditory cortex is thus a powerful discovery platform with which to identify mediators of tonotopic plasticity.

Reduction of NgR in perforant path decreases amyloid-ß peptide production and ameliorates synaptic and cognitive deficits in APP/PS1 mice.

BACKGROUND: Amyloid beta (Aß) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied. METHODS: To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP). RESULTS: It is shown that reduction of NgR in the perforant path rescued cognitive and synaptic deficits in APP/PS1 transgenic mice. Concurrently, Aß production in the perforant path and levels of soluble Aß and amyloid plaques in the hippocampus were significantly decreased. There was a positive correlation between the total APP protein level and NgR expression both in transgenic mice and in cultured cells, where the α-secretase and ß-secretase cleavage products both changed with APP level in parallel. Finally, NgR might inhibit APP degradation through lysosome by Rho/Rho-associated protein kinases (ROCK) signaling pathway. CONCLUSIONS: Our findings demonstrate that perforant path NgR plays an important role in regulating APP/Aß level and cognitive functions in AD transgenic mice, which might be related to the suppression of APP degradation by NgR. Our study suggests that NgR in the perforant path could be a potential target for modulating AD progression.

Static Leukoencephalopathy Associated with 17p13.3 Microdeletion Syndrome: A Case Report.

BACKGROUND: Leukoencephalopathy associated with dysmorphic features may be attributed to chromosomal abnormalities such as 17p13.3 microdeletion syndrome. CASE: A 19-year-old female patient was referred to our hospital for diagnostic evaluation of her leukoencephalopathy. She demonstrated moderate intellectual disability, minor dysmorphic features, and short stature. Serial brain magnetic resonance images obtained within a 16-year interval revealed prolonged T2 signals in the deep cerebral white matter with enlarged Virchow-Robin spaces. A nonsymptomatic atlas anomaly was also noted. Using microarray-based comparative genomic hybridization, we identified a 2.2-Mb terminal deletion at 17p13.3, encompassing YWHAE, CRK, and RTN4RL1 but not PAFAH1B1. CONCLUSION: Except for atlas anomaly, the patient's clinical and imaging findings were compatible with the diagnosis of 17p13.3 microdeletion syndrome. The white matter abnormality was static and nonprogressive. The association between the atlas abnormality and this deletion remains elusive. We note the importance of exploring submicroscopic chromosomal imbalance when patients show prominent but static white matter abnormalities with discrepantly mild and stable neurological signs.

Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66/NgR-independent targeting of NogoA.

NogoA inhibits neurite outgrowth of motoneurons (NOM) through interaction with its receptors, Nogo66/NgR. Inhibition of Nogo receptors rescues NOM, but not to the extent exhibited by NogoA-knockout mice, suggesting the presence of other pathways. We found that NogoA-overexpressing muscle cells reduced phosphoglycerate kinase 1 (Pgk1) secretion, resulting in inhibiting NOM. Apart from its glycolytic role and independent of the Nogo66 pathway, extracellular Pgk1 stimulated NOM by triggering a reduction of p-Cofilin-S3, a growth cone collapse marker, through decreasing a novel Rac1-GTP/p-Pak1-T423/p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 molecular pathway. Not only did supplementary Pgk1 enhance NOM in defective cells, but injection of Pgk1 rescued denervation in muscle-specific NogoA-overexpression of zebrafish and an Amyotrophic Lateral Sclerosis mouse model, SOD1 G93A. Thus, Pgk1 secreted from muscle is detrimental to motoneuron neurite outgrowth and maintenance.