Neuropathogenesis-on-chips for neurodegenerative diseases.

Developing diagnostics and treatments for neurodegenerative diseases (NDs) is challenging due to multifactorial pathogenesis that progresses gradually. Advanced in vitro systems that recapitulate patient-like pathophysiology are emerging as alternatives to conventional animal-based models. In this review, we explore the interconnected pathogenic features of different types of ND, discuss the general strategy to modelling NDs using a microfluidic chip, and introduce the organoid-on-a-chip as the next advanced relevant model. Lastly, we overview how these models are being applied in academic and industrial drug development. The integration of microfluidic chips, stem cells, and biotechnological devices promises to provide valuable insights for biomedical research and developing diagnostic and therapeutic solutions for NDs.

Implementation of the neuro-glia-vascular unit through co-culture of adult neural stem cells and vascular cells and transcriptomic analysis of diverse Aß assembly types.

BACKGROUND: The blood-brain barrier (BBB) is a specialized layer between blood vessels and tissue in the brain, which is comprised of a neuro-glia-vascular (NGV) unit, thus play a vital role in various brain diseases. NEW METHOD: We developed the in vitro NGV units by co-culturing brain microvascular endothelial cells (BMECs; bEnd.3) and primary neural stem cells extracted from subventricular zone of adult mice. This approach was designed to mimic the RNA profile conditions found in the microvessels of a mouse brain and confirmed through various comparative transcriptome analyses. RESULTS: Optimal NGV unit development was achieved by adjusting cell density-dependent co-culture ratios. Specifically, the morphogenic development and neuronal association of astrocyte endfeet were well observed in the contact region with BMECs in the NGV unit. Through transcriptome analysis, we compared co-cultured bEnd.3/NSCs with monocultured bEnd.3 or NSCs and additionally compared them with previously reported mouse brain vascular tissue to show that this NGV unit model is a suitable in vitro model for neurological disease such as Alzheimer's disease (AD). COMPARISON WITH EXISTING METHOD(S): This in vitro NGV unit was formed from neural stem cells and vascular cells in the brain of adult mice, not embryos. It is very useful for studying brain disease mechanisms by identifying proteins and genes associated with diseases progress. CONCLUSIONS: We suggest that this simple in vitro NGV model is appropriate to investigate the relationship between BBB changes and pathological factors in the fields of neurovascular biology and cerebrovascular diseases including AD.

Anti-inflammatory effects of neuregulin-1 in HaCaT keratinocytes and atopic dermatitis-like mice stimulated with Der p 38.

Neuregulin (NRG)-1 plays fundamental roles in several organ systems after binding to its receptors, ErbB2 and ErbB4. This study examines the role of NRG-1 in atopic dermatitis (AD), a chronic skin disease that causes dryness, pruritus, and inflammation. In mice administered Der p 38, the skin presents AD-like symptoms including filaggrin downregulation and infiltration of neutrophils and eosinophils. Noticeably, there is an increased expression of NRG-1, ErbB2, and ErbB4 in the skin. Upregulation of these proteins is significantly correlated to the clinical skin severity score. In human keratinocyte HaCaT cells, exposure to Der p 38 decreased filaggrin expression, and NRG-1 alone had no effect on the expression. However, co-treatment of Der p 38 with NRG-1 enhanced the filaggrin expression decreased by Der p 38. Pre-treatment with AG879 (an ErbB2 inhibitor) or ErbB4 siRNA blocked the recovery of filaggrin expression in the cells after co-treatment with Der p 38 and NRG-1. Der p 38 treatment enhanced the secretion of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1). Co-treatment of Der p 38 with NRG-1 lowered the cytokine secretion increased by Der p 38, although NRG-1 alone was not effective on cytokine alteration. Neutrophil apoptosis was not altered by NRG-1 or supernatants of cells treated with NRG-1, but the cell supernatants co-treated with Der p 38 and NRG-1 blocked the anti-apoptotic effects of Der p 38-treated supernatants on neutrophils, which was involved in the activation of caspase 9 and caspase 3. Taken together, we determined that NRG-1 has anti-inflammatory effects in AD triggered by Der p 38. These results will pave the way to understanding the functions of NRG-1 and in the future development of AD treatment.

Multiple low-dose radiation-induced neuronal cysteine transporter expression and oxidative stress are rescued by N-acetylcysteine in neuronal SH-SY5Y cells.

Recently, several studies have demonstrated that low-dose radiation (LDR) therapy has positively impacts on the treatment of Alzheimer's disease (AD). LDR suppresses the production of pro-neuroinflammation molecules and improves cognitive function in AD. However, it is unclear whether direct exposure to LDR causes beneficial effects and what mechanism is involved in neuronal cells. In this study, we first determined the effect of high-dose radiation (HDR) alone on C6 cells and SH-SY5Y cells. We found that SH-SY5Y cells were more vulnerable than C6 cells to HDR. Moreover, in neuronal SH-SY5Y cells exposed to single or multiple LDR, N-type cells showed decreased cell viability with increasing radiation exposure time and frequency, but S-type cells were unaffected. Multiple LDR increased proapoptotic molecules such as p53, Bax and cleaved caspase-3, and decreased anti-apoptotic molecule (Bcl2). Multiple LDR also generated free radicals in neuronal SH-SY5Y cells. We detected a change in the expression of the neuronal cysteine transporter EAAC1. Pretreatment with N-acetylcysteine (NAC) rescued the increased in EAAC1 expression and the generation of ROS in neuronal SH-SY5Y cells after multiple LDR. Furthermore, we verified whether the increased in EAAC1 expression induces cell defense or cell death promotion signaling. We showed that transient overexpression of EAAC1 reduced the multiple LDR-induced p53 overexpression in neuronal SH-SY5Y cells. Our results indicate that neuronal cells can be injured by increased production of ROS not only by HDR but also by multiple LDR, which suggests that combination treatment with anti-free radical agents such as NAC may be useful in multiple LDR therapy.

Neuregulin-1 reverses anxiety-like behavior and social behavior deficits induced by unilateral micro-injection of CoCl2 into the ventral hippocampus (vHPC).

Neuregulin-1 (NRG1) is an epidermal growth factor family member with essential roles in the developing and adult nervous systems. In recent years, establishing evidence has collectively suggested that NRG1 is a new modulator of central nervous system (CNS) injury and disease, with multifaceted roles in neuroprotection, remyelination, neuroinflammation, and other repair mechanisms. NRG1 signaling exerts its effects via the tyrosine kinase receptors ErbB2-ErbB4. The NRG1/ErbB network in CNS pathology and repair has evolved, primarily in recent years. In the present study, we demonstrated that a unilateral microinjection of CoCl2 into the ventral hippocampus (vHPC) induced hypoxic insult and led to anxiety-related behaviors and deficit sociability in mice. NRG1 treatment significantly alleviated the CoCl2-induced increase of hypoxic-related molecules and behavioral abnormalities. Furthermore, NRG1 reduced the CoCl2-induced neuroinflammation and neuronal deficits in the vHPC or primary hippocampal neurons in mice. Collectively, these results suggest that NRG1 ameliorates hypoxia by alleviating synaptic deficits and behavioral abnormalities of the CoCl2-induced vHPC hypoxic model.

Exploring medical students' perception of non-face-to-face theory and face-to-face laboratory classes during COVID-19 pandemic: focusing on anatomy course.

PURPOSE: This study investigated students' perceptions of non-face-to-face theory classes and face-to-face laboratory classes conducted in anatomy courses at medical schools during the coronavirus disease 2019 pandemic. METHODS: This study utilized a questionnaire to assess self-reported academic achievement level, satisfaction with non-face-to-face theory classes, satisfaction with face-to-face laboratory classes, and self-directed learning level, and conducted difference verification and regression analysis for 51 students who took anatomy courses from the fall semester of 2020 to the spring semester of 2021. RESULTS: The group with a high self-reported academic achievement level was more satisfied with the non-face-to-face theory classes than the group with a low self-reported academic achievement level. The group with a high self-reported academic achievement level had a higher self-directed learning level than the group with a low self-reported academic achievement level. In addition, it was found that the higher the self-directed learning level, the higher the satisfaction with non-face-to-face theory classes. CONCLUSION: These results suggest that to enhance satisfaction with non-face-to-face theory classes in an anatomy course, a favorable class environment that can increase the self-directed learning level is needed. In particular, careful concern is required when designing non-face-to-face classes for students with a low self-reported academic achievement.

A new brain-cutting device and ultraviolet resin-mounted human brain slices as a teaching adjunct for neuroanatomy education.

Although the level of neuroscience research is rapidly developing with the introduction of new technologies, the method of neuroanatomy education remains at the traditional level and requires improvement to meet the needs of educators and trainees. We developed a new three-dimensional (3D) printed device (human brain-cutting mold, HBCM) for creating human brain slices; moreover, we demonstrated a simple method for creating semi-permanent ultraviolet (UV) resin-mounted brain slice specimens for neuroanatomy education. We obtained brain slices of uniform thickness (3 mm) through the HBCM; the resultant brain slices were optimal for assessing morphological details of the human brain. Furthermore, we used an agar-embedding method for brain-slicing with the HBCM, which minimized geometrical distortions of the brain slices. Also, we prepared semi-permanent brain serial specimens using an acrylic brain slice frame and UV-curable resin, which was highly compatible with moist bio-specimens. During UV resin curing, neither air bubble formation nor color change occurred. The resultant UV resin-mounted brain slices produced definite coronal sections with high transparency and morphological accuracy. We also performed 3D modeling by stacking brain slice images that differentiated the cortical area and nine subcortical regions via manual segmentation. This method could be a reliable alternative for displaying high-quality human brain slices and would be helpful for students and trainee to understand anatomical orientation from 2D images to 3D structures. Also, this may present an innovative approach for preparing and preserving coronal sections of the normal or pathological human brain.

Transcriptomic analysis in the striatum reveals the involvement of Nurr1 in the social behavior of prenatally valproic acid-exposed male mice.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that exhibits neurobehavioral deficits characterized by abnormalities in social interactions, deficits in communication as well as restricted interests, and repetitive behaviors. The basal ganglia is one of the brain regions implicated as dysfunctional in ASD. In particular, the defects in corticostriatal function have been reported to be involved in the pathogenesis of ASD. Surface deformation of the striatum in the brains of patients with ASD and their correlation with behavioral symptoms was reported in magnetic resonance imaging (MRI) studies. We demonstrated that prenatal valproic acid (VPA) exposure induced synaptic and molecular changes and decreased neuronal activity in the striatum. Using RNA sequencing (RNA-Seq), we analyzed transcriptome alterations in striatal tissues from 10-week-old prenatally VPA-exposed BALB/c male mice. Among the upregulated genes, Nurr1 was significantly upregulated in striatal tissues from prenatally VPA-exposed mice. Viral knockdown of Nurr1 by shRNA significantly rescued the reduction in dendritic spine density and the number of mature dendritic spines in the striatum and markedly improved social deficits in prenatally VPA-exposed mice. In addition, treatment with amodiaquine, which is a known ligand for Nurr1, mimicked the social deficits and synaptic abnormalities in saline-exposed mice as observed in prenatally VPA-exposed mice. Furthermore, PatDp+/- mice, a commonly used ASD genetic mouse model, also showed increased levels of Nurr1 in the striatum. Taken together, these results suggest that the increase in Nurr1 expression in the striatum is a mechanism related to the changes in synaptic deficits and behavioral phenotypes of the VPA-induced ASD mouse model.

Der f 38 Is a Novel TLR4-Binding Allergen Related to Allergy Pathogenesis from Dermatophagoides farinae.

It is difficult to treat allergic diseases including asthma completely because its pathogenesis remains unclear. House dust mite (HDM) is a critical allergen and Toll-like receptor (TLR) 4 is a member of the toll-like receptor family, which plays an important role in allergic diseases. The purpose of this study was to characterize a novel allergen, Der f 38 binding to TLR4, and unveil its role as an inducer of allergy. Der f 38 expression was detected in the body and feces of Dermatophagoides farinae (DF). Electron microscopy revealed that it was located in the granule layer, the epithelium layer, and microvilli of the posterior midgut. The skin prick test showed that 60% of allergic subjects were Der f 38-positive. Der f 38 enhanced surface 203c expression in basophils of Der f 38-positive allergic subjects. By analysis of the model structure of Der p 38, the expected epitope sites are exposed on the exterior side. In animal experiments, Der f 38 triggered an infiltration of inflammatory cells. Intranasal (IN) administration of Der f 38 increased neutrophils in the lung. Intraperitoneal (IP) and IN injections of Der f 38 induced both eosinophils and neutrophils. Increased total IgE level and histopathological features were found in BALB/c mice treated with Der f 38 by IP and IN injections. TLR4 knockout (KO) BALB/c mice exhibited less inflammation and IgE level in the sera compared to wild type (WT) mice. Der f 38 directly binds to TLR4 using biolayer interferometry. Der f 38 suppressed the apoptosis of neutrophils and eosinophils by downregulating proteins in the proapoptotic pathway including caspase 9, caspase 3, and BAX and upregulating proteins in the anti-apoptotic pathway including BCL-2 and MCL-1. These findings might shed light on the pathogenic mechanisms of allergy to HDM.

Neuregulin 1/ErbB4/Akt signaling attenuates cytotoxicity mediated by the APP-CT31 fragment of amyloid precursor protein.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by neuronal and synaptic loss. The cytoplasmic tail of amyloid precursor protein (APP) undergoes sequential cleavage at a specific intracellular caspase site to generate the cytoplasmic terminal 31 (CT31) fragment. The APP-CT31 fragment is a potent inducer of apoptosis. The cytotoxicity of APP-CT31 in SH-SY5Y cells was evaluated by the lactate dehydrogenase (LDH) assay. TUNEL staining was used to detect apoptotic signals in SH-SY5Y cells and primary cortical neurons. The expression of apoptosis-related proteins, such as p53, PUMA (p53 up-regulated modulator of apoptosis), and cleaved was investigated by immunofluorescence analysis and Western blotting. In this study, we investigated the neuroprotective effect of neuregulin 1 (NRG1) against cytotoxicity induced by APP-CT31. Our data showed that CT31 induced cytotoxicity and apoptosis in SH-SY5Y cells and primary cortical neurons. NRG1 attenuated the neurotoxicity induced by the expression of APP-CT31. We also showed that APP-CT31 altered the expression of p53 and cleaved caspase 3. However, treatment with NRG1 rescued the APP-CT31-induced upregulation of p53 and cleaved caspase 3 expression. The protective effect of NRG1 was abrogated by inhibition of the ErbB4 receptor and Akt. These results indicate an important role of ErbB4/Akt signaling in NRG1-mediated neuroprotection, suggesting that endogenous NRG1/ErbB4 signaling represents a valuable therapeutic target in AD.

Neuregulin-1 inhibits CoCl2-induced upregulation of excitatory amino acid carrier 1 expression and oxidative stress in SH-SY5Y cells and the hippocampus of mice.

Excitatory amino acid carrier 1 (EAAC1) is an important subtype of excitatory amino acid transporters (EAATs) and is the route for neuronal cysteine uptake. CoCl2 is not only a hypoxia-mimetic reagent but also an oxidative stress inducer. Here, we found that CoCl2 induced significant EAAC1 overexpression in SH-SY5Y cells and the hippocampus of mice. Transient transfection of EAAC1 reduced CoCl2-induced cytotoxicity in SH-SY5Y cells. Based on this result, upregulation of EAAC1 expression by CoCl2 is thought to represent a compensatory response against oxidative stress in an acute hypoxic state. We further demonstrated that pretreatment with Neuregulin-1 (NRG1) rescued CoCl2-induced upregulation of EAAC1 and tau expression. NRG1 plays a protective role in the CoCl2-induced accumulation of reactive oxygen species (ROS) and reduction in antioxidative enzyme (SOD and GPx) activity. Moreover, NRG1 attenuated CoCl2-induced apoptosis and cell death. NRG1 inhibited the CoCl2-induced release of cleaved caspase-3 and reduction in Bcl-XL levels. Our novel finding suggests that NRG1 may play a protective role in hypoxia through the inhibition of oxidative stress and thereby maintain normal EAAC1 expression levels.

Early-life stress induces EAAC1 expression reduction and attention-deficit and depressive behaviors in adolescent rats.

Neonatal maternal separation (NMS), as an early-life stress (ELS), is a risk factor to develop emotional disorders. However, the exact mechanisms remain to be defined. In the present study, we investigated the mechanisms involved in developing emotional disorders caused by NMS. First, we confirmed that NMS provoked impulsive behavior, orienting and nonselective attention-deficit, abnormal grooming, and depressive-like behaviors in adolescence. Excitatory amino acid carrier 1 (EAAC1) is an excitatory amino acid transporter expressed specifically by neurons and is the route for the neuronal uptake of glutamate/aspartate/cysteine. Compared with that in the normal control group, EAAC1 expression was remarkably reduced in the ventral hippocampus and cerebral cortex in the NMS group. Additionally, EAAC1 expression was reduced in parvalbumin-positive hippocampal GABAergic neurons in the NMS group. We also found that EAAC1-knockout (EAAC1-/-) mice exhibited impulsive-like, nonselective attention-deficit, and depressive-like behaviors compared with WT mice in adolescence, characteristics similar to those of the NMS behavior phenotype. Taken together, our results revealed that ELS induced a reduction in EAAC1 expression, suggesting that reduced EAAC1 expression is involved in the pathophysiology of attention-deficit and depressive behaviors in adolescence caused by NMS.

Neuregulin-1 Protects Neuronal Cells Against Damage due to CoCl2-Induced Hypoxia by Suppressing Hypoxia-Inducible Factor-1α and P53 in SH-SY5Y Cells.

PURPOSE: Hypoxia-mediated neurotoxicity contributes to various neurodegenerative disorders, including Alzheimer disease. Neuregulin-1 (NRG1) plays an important role in the development and plasticity of the brain. The aim of the present study was to investigate the neuroprotective effect and the regulating hypoxic inducible factor of NRG1 in cobalt chloride (CoCl2) induced hypoxia. METHODS: Hypoxia was induced in SH-SY5Y cells by CoCl2 treatment. SH-SY5Y cells were pretreated with NRG1 and then treated with CoCl2. Western blotting, immunocytochemistry, and lactate dehydrogenase (LDH) release assays were performed to examine neuroprotective properties of NRG1 in SH-SY5Y cells. RESULTS: Our data showed that CoCl2 induced cytotoxicity and changes of hypoxia-inducible factor-1α (HIF-1α) and p53 expression in SH-SY5Y cells. However, pretreatment with NRG1 inhibited CoCl2-induced accumulation of HIF-1α and p53 stability. In addition, NRG1 significantly attenuated cell death of SH-SY5Y induced by CoCl2. CONCLUSION: NRG1 can regulate HIF-1α and p53 to protect neurons against hypoxic damage.

A rare bilateral variation on the dorsum of the hand: extensor digitorum brevis manus and extensor medii proprius.

A 78-year-old male cadaver showed bilateral anomalous muscles on the dorsum of the hand. An extensor digitorum brevis manus was noted on the dorsum of the right hand. It originated from the distal end of the radius and the radiocarpal joint ligaments and inserted into the metacarpophalangeal joint of the third digit. On the dorsum of the left hand, an extensor digiti medii proprius was identified. It originated from the distal third of the ulna near the extensor indicis proprius and the interosseous membrane and inserted into the metacarpophalangeal joint of the third digit. Awareness of these combined muscular variation would be helpful in understanding the identification of digital extensors and in requiring careful consideration for the reconstruction surgery of the hand.

Neuregulin 1/ErbB4 signaling attenuates neuronal cell damage under oxygen-glucose deprivation in primary hippocampal neurons.

The hippocampus is one of the most important brain areas of cognition. This region is particularly sensitive to hypoxia and ischemia. Neuregulin-1 (NRG1) has been shown to be able to protect against focal cerebral ischemia. The aim of the present study was to investigate the neuroprotective effect of NRG1 in primary hippocampal neurons and its underlying mechanism. Our data showed oxygen-glucose deprivation (OGD)-induced cytotoxicity and overexpression of ErbB4 in primary hippocampal neurons. Moreover, pretreatment with NRG1 could inhibit OGD-induced overexpression of ErbB4. In addition, NRG1 significantly attenuated neuronal death induced by OGD. The neuroprotective effect of NRG1 was blocked in ischemic neurons after pretreatment with AG1478, an inhibitor of ErbB4, but not after pretreatment with AG879, an inhibitor of ErbB2. These results indicate an important role of ErbB4 in NRG1-mediated neuroprotection, suggesting that endogenous ErbB4 might serve as a valuable therapeutic target for treating global cerebral ischemia.

Neuregulin1 Attenuates H2O2-Induced Reductions in EAAC1 Protein Levels and Reduces H2O2-Induced Oxidative Stress.

Neuregulin 1 (NRG1) exhibits potent neuroprotective properties. The aim of the present study was to investigate the antioxidative effects and underlying mechanisms of NRG1 against H2O2-induced oxidative stress in primary rat cortical neurons. The expression level of the excitatory amino acid carrier 1 (EAAC1) protein was measured by Western blotting and immunocytochemistry. The levels of lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity, GPx activity, and mitochondrial membrane potential (∆ψm) were determined to examine cell death and the antioxidant properties of NRG1 in primary rat cortical neurons. H2O2 reduced the expression of EAAC1 in a dose-dependent manner. We found that pretreatment with NRG1 attenuated the H2O2-induced reduction in EAAC1 expression. Moreover, NRG1 reduced the cell death and oxidative stress induced by H2O2. In addition, NRG1 attenuated H2O2-induced reductions in antioxidant enzyme activity and ∆ψm. Our data indicate a role for NRG1 in protecting against oxidative stress via the regulation of EAAC1. These observations may provide novel insights into the mechanisms of NRG1 activity during oxidative stress and may reveal new therapeutic targets for regulating the oxidative stress associated with various neurological diseases.

Neuregulin 1 regulates amyloid precursor protein cell surface expression and non-amyloidogenic processing.

The amyloid precursor protein (APP) is a key molecule in Alzheimer's disease. The prevailing view is that APP is initially transported to the plasma membrane as a full-length protein. Its localization at the cell surface can trigger downstream signaling and APP cleavage. Our previous work has shown that Neuregulin 1 (NRG1) has neuroprotective effects in an Alzheimer's disease model. In the present study, we examine whether NRG1 signaling is involved in APP expression and non-amyloidogenic processing in neuronal cells. Here we show that NRG1 increased the cell surface expression of APP without changing the total amount of APP mRNA or protein expression in SH-SY5Y cells and in rat primary cortical neurons. In addition, NRG1 significantly increased the levels of the secreted form of APP, sAPPα, in the conditioned media but did not change the expression of ADAM10 on the cell surface or in the cell lysates. Furthermore, we found that the protein level of NRG1 was reduced in the hippocampus of Alzheimer's disease (AD) patients. Our results demonstrate that NRG1 increased APP expression on the cell surface and sAPPα secretion into the media of neuronal cell cultures. Taken together, these results suggest a role for NRG1 in non-amyloidogenic processing.

Neuroanatomical distribution of galectin-3 in the adult rat brain.

Galectin-3 is a member of the lectin subfamily that enables the specific binding of ß-galactosides. It is expressed in a broad spectrum of species and organs, and is known to have various functions related to cell adhesion, signal transduction, and proinflammatory responses. Although, expression of galectin-3 in some activated neuroglia under neuroinflammation has been well documented in the central nervous system, little is known about the neuronal expression and distribution of galectin-3 in normal brain. To describe the cellular and neuroanatomical expression map of galectin-3, we performed galectin-3 immunohistochemistry on the entire normal rat brain and subsequently analyzed the neuronal distribution. Galectin-3 expression was observed not only in some neuroglia but also in neurons. Neuronal expression of galectin-3 was observed in many functional parts of the cerebral cortex and various other subcortical nuclei in the hypothalamus and brainstem. Neuroanatomical analysis revealed that robust galectin-3 immuno-signals were present in many hypothalamic nuclei related to a variety of physiological functions responsible for mediating anxiety responses, energy balance, and neuroendocrine regulation. In addition, the regions highly connected with these hypothalamic nuclei also showed intense galectin-3 expression. Moreover, multiple key regions involved in regulating autonomic functions exhibited high levels of galectin-3 expression. In contrast, the subcortical nuclei responsible for the control of voluntary motor functions and limbic system exhibited no galectin-3 immunoreactivity. These observations suggest that galectin-3 expression in the rat brain seems to be regulated by developmental cascades, and that functionally and neuroanatomically related brain nuclei constitutively express galectin-3 in adulthood.

Blocking the phosphatidylinositol 3-kinase pathway inhibits neuregulin-1-mediated rescue of neurotoxicity induced by Aß1-42.

OBJECTIVES: Neuregulin-1 (NRG1) has an important role in both the development and the plasticity of the brain as well as neuroprotective properties. In this study, we investigated the downstream pathways of NRG1 signalling and their role in the prevention of Aß1-42 -induced neurotoxicity. METHODS: Lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) generation, superoxide dismutase (SOD) activity and TUNEL staining were assayed to examine the neuroprotective properties in primary rat cortical neurons. KEY FINDINGS: The inhibition of PI3K/Akt activation abolished the ability of NRG1 to prevent Aß1-42 -induced LDH release and increased TUNEL-positive cell count and reactive oxygen species accumulation in primary cortical neurons. CONCLUSIONS: Our results demonstrate that NRG1 signalling exerts a neuroprotective effect against Aß1-42 -induced neurotoxicity via activation of the PI3K/Akt pathway. Furthermore, this suggests that NRG1 has neuroprotective potential for the treatment of AD.