Spinal Cord Injury and Postdural Puncture Headache following Cervical Interlaminar Epidural Steroid Injection: A Case Report.

Background: Cervical interlaminar epidural steroid injection (CIESI) is increasingly used as an interventional treatment for pain originating from the cervical spine. However, serious neurological complications may occur during CIESI because of direct nerve damage following inappropriate needle placement. Case report: A 35-year-old woman presented with posterior neck pain radiating to the left upper arm. Cervical magnetic resonance imaging (MRI) revealed left C6 nerve impingement. CIESI under fluoroscopic guidance was performed at another hospital using the left C5/6 interlaminar approach. Immediately after the procedure, the patient experienced dizziness, decreased blood pressure, motor weakness in the left upper arm, and sensory loss. She visited our emergency department with postdural puncture headache (PDPH) that worsened after the procedure. Post-admission cervical MRI revealed intramedullary T2 high signal intensity and cord swelling from the C4/5 to C6/7 levels; thus, a diagnosis of spinal cord injury was made. The patient's PDPH spontaneously improved after 48 h. However, despite conservative treatment with steroids, the decrease in abduction of the left fifth finger and loss of sensation in the dorsum of the left hand persisted for up to 6 months after the procedure. As noticed in the follow-up MRI performed 6 months post-procedure, the T2 high signal intensity in the left intramedullary region had decreased compared to that observed previously; however, cord swelling persisted. Furthermore, left C7/8 radiculopathy with acute denervation was confirmed by electromyography performed 6 months after the procedure. Conclusions: Fluoroscopy does not guarantee the prevention of spinal cord penetration during CIESI. Moreover, persistent neurological deficits may occur, particularly due to intrathecal perforation or drug administration during CIESI. Therefore, in accordance with the recommendations of the Multisociety Pain Workgroup, we recommend performing CIESI at the C6/7 or C7/T1 levels, where the epidural space is relatively large, rather than at the C5/6 level or higher.

Depletion of Mitochondrial Components from Extracellular Vesicles Secreted from Astrocytes in a Mouse Model of Fragile X Syndrome.

Mitochondrial dysfunction contributes to neurodegenerative diseases and developmental disorders such as Fragile X syndrome (FXS). The cross-talk between mitochondria and extracellular vesicles (EVs) suggests that EVs may transfer mitochondrial components as intermediators for intracellular communication under physiological and pathological conditions. In the present study, the ability of EVs to transfer mitochondrial components and their role in mitochondrial dysfunction in astrocytes were examined in the brains of Fmr1 knockout (KO) mice, a model of FXS. The amounts of mitochondrial transcription factor NRF-1, ATP synthases ATP5A and ATPB, and the mitochondrial membrane protein VDAC1 in EVs were reduced in cerebral cortex samples and astrocytes from Fmr1 KO mice. These reductions correspond to decreased mitochondrial biogenesis and transcriptional activities in Fmr1 KO brain, along with decreased mitochondrial membrane potential (MMP) with abnormal localization of vimentin intermediate filament (VIF) in Fmr1 KO astrocytes. Our results suggest that mitochondrial dysfunction in astrocytes is associated with the pathogenesis of FXS and can be monitored by depletion of components in EVs. These findings may improve the ability to diagnose developmental diseases associated with mitochondrial dysfunction, such as FXS and autism spectrum disorders (ASD).

G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination.

GPR56, an orphan G protein-coupled receptor (GPCR) from the family of adhesion GPCRs, plays an indispensable role in cortical development and lamination. Mutations in the GPR56 gene cause a malformed cerebral cortex in both humans and mice that resembles cobblestone lissencephaly, which is characterized by overmigration of neurons beyond the pial basement membrane. However, the molecular mechanisms through which GPR56 regulates cortical development remain elusive due to the unknown status of its ligand. Here we identify collagen, type III, alpha-1 (gene symbol Col3a1) as the ligand of GPR56 through an in vitro biotinylation/proteomics approach. Further studies demonstrated that Col3a1 null mutant mice exhibit overmigration of neurons beyond the pial basement membrane and a cobblestone-like cortical malformation similar to the phenotype seen in Gpr56 null mutant mice. Functional studies suggest that the interaction of collagen III with its receptor GPR56 inhibits neural migration in vitro. As for intracellular signaling, GPR56 couples to the Gα(12/13) family of G proteins and activates RhoA pathway upon ligand binding. Thus, collagen III regulates the proper lamination of the cerebral cortex by acting as the major ligand of GPR56 in the developing brain.

Policy Analysis for Implementing Neuroethics in Korea's Brain Research Promotion Act.

In 1998, Korea implemented the Brain Research Promotion Act (BRPA), a law to revamp the field of neuroscience at the national level. However, despite numerous revisions including the definition and classification of neuroscience and the national plans for the training and education systems, the governance for neuroethics has not been integrated into the Act. The ethical issues raised by neuroscience and neurotechnology remain unchallenged, especially given the focus on the industrial purpose of the technology. In the current study, we analyzed the BRPA revision process by using Kingdon's Multiple Streams Framework to determine the problems faced by the process. We propose a new strategy, including neuroethics governance and a national committee, to promote interdisciplinary neuroscience research and strengthen neuroethics in Korea.

Isolation and identification of extracellular matrix proteins from oil-based CASPERized mouse brains for matrisomal analysis.

The extracellular matrix (ECM) components present within all tissues and organs help to maintain the cytoskeletal architecture and tissue morphology. Although the ECM plays a role in cellular events and signaling pathways, it has not been well studied due its insolubility and complexity. Brain tissue has a higher cell density and weaker mechanical strength than other tissues in the body. When removing cells using a general decellularization method to produce scaffolds and obtain ECM proteins, various problems must be considered because tissues are easily damaged. To retain the brain shape and ECM components, we performed decellularization in combination with polymerization. We immersed mouse brains in oil for polymerization and decellularization via O-CASPER (Oil-based Clinically and Experimentally Applicable Acellular Tissue Scaffold Production for Tissue Engineering and Regenerative Medicine) and then isolated ECM components using sequential matrisome preparation reagents (SMPRs), namely, RIPA, PNGase F, and concanavalin A. Adult mouse brains were preserved with our decellularization method. Western blot and LC-MS/MS analyses revealed that ECM components, including collagen and laminin, were isolated efficiently from decellularized mouse brains using SMPRs. Our method will be useful to obtain matrisomal data and perform functional studies using adult mouse brains and other tissues.

The role of STAT3 activation in modulating the immune microenvironment of GBM.

Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.

Risk factors for new vertebral compression fracture after kyphoplasty and efficacy of osteoporosis treatment: A STROBE-compliant retrospective study.

Kyphoplasty (KP) has been widely used to treat vertebral compression fractures (VCFs). However, the issue of new VCFs after KP remains controversial. Identification of risk factors for new VCF after KP may help prevent their occurrence in patients. This study aimed to retrospectively determine the major risk factors for new VCF after KP, including those associated with osteoporosis drugs used after kyphoplasty. We reviewed 117 patients who underwent single-level KP. During the follow-up period of 1 year after KP, the demographic data of these patients were compared by dividing them into two groups: those with new fractures (n = 19) and those without new fractures (n = 98). We investigated the age, sex, fracture location, medical history, steroid use history, bone mineral density (BMD), type of osteoporosis treatment, period from fracture to KP, KP method (unilateral or bilateral), bone cement dose, intradiscal cement leakage, preoperative and postoperative compression ratio, kyphotic angle (KA), and lowest vertebral body height in the fractured vertebrae. Based on these data, the factors related to new VCFs after KP were investigated using univariate and multivariate logistic regression analyses. We also investigated whether there were differences in new VCFs according to the type of osteoporosis treatment. During the 1-year follow-up period after KP, the rate of new VCFs was 16.2%. Factors related to new VCFs were BMD, intradiscal cement leakage, KA recovery rate after 1 day, and baseline height in the univariate and multivariate logistic regression analyses. The group treated with zoledronate after KP tended to show a lower frequency of developing new VCFs than the groups treated with alendronate (P = .07), calcium (P = .05), selective estrogen receptor modulator (SERM) (P = .15), and risendronate (P = .02). This study showed that for patients with new VCFs after KP, lower BMD, greater intradiscal cement leakage, greater KA recovery rate, and lower baseline vertebral height were likely risk factors for the development of new VCFs. Additionally, among the drugs used for the treatment of osteoporosis after KP, zoledronate tends to reduce the development of new VCFs compared with other bisphosphonates, SERMs, or calcium.

Prediction of outcomes after radical prostatectomy in patients diagnosed with prostate cancer of biopsy Gleason score ≥ 8 via contemporary multi (≥ 12)-core prostate biopsy.

OBJECTIVE: • To investigate the outcome of patients who underwent radical prostatectomy (RP) for prostate cancer of biopsy Gleason score ≥ 8 diagnosed via contemporary prostate biopsy. PATIENTS AND METHODS: • We reviewed records of 151 patients who underwent RP for prostate cancer of biopsy Gleason score ≥ 8 detected via multi (≥ 12)-core prostate biopsy without any neoadjuvant or adjuvant treatment. • Preoperative predictors of pathologically organ-confined disease along with biochemical recurrence-free survival were analyzed via multivariate logistic regression and Cox proportional hazards model. RESULTS: • For 151 total subjects, 5-year estimated biochemical recurrence-free survival rate was 41.0%. Patients with pathologically organ-confined disease were observed to have much higher 5-year biochemical recurrence-free survival rate than those otherwise (72.1 vs 31.5%, P < 0.001). • Serum PSA level (P= 0.031) and maximum tumour length in a biopsy core (P= 0.005) were observed to be significant preoperative predictors of having pathologically organ-confined disease. • As for biochemical recurrence-free survival following RP, serum PSA (P= 0.023), biopsy Gleason score (P= 0.032), and percent of total tumour length in biopsy cores (P < 0.001) were observed be significant preoperative predictors on multivariate analysis. CONCLUSION: • Among contemporary patients with biopsy Gleason score ≥ 8 who underwent RP alone, patients with pathologically organ-confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ-confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥ 8.

Is body mass index associated with pathological outcomes after radical prostatectomy in Korean men?

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Today, controversies continue with regards to the potential impact of obesity or increased body mass index (BMI) on actual pathological features of prostate cancer and/or clinical outcome after radical prostatectomy (RP). Moreover, a paucity of relevant data exist in the literature regarding Asian or Korean men. For the first time to our knowledge, the study demonstrated that although higher BMI was significantly associated with extracapsular extension of tumour, BMI did not significantly enhance ability to preoperatively predict extracapsular extension of tumour and was not significantly associated with PSA outcome as well as other objective pathological outcomes in Korean men undergoing RP, who are generally leaner than Western counterparts. OBJECTIVE: • To investigate the impact of increased body mass index (BMI) on pathological features after radical prostatectomy (RP) in Korean patients. PATIENTS AND METHODS: • We reviewed the records of 1000 Korean patients who underwent RP for prostate cancer and assessed the differences in pathological outcomes and biochemical recurrence-free survival after RP according to BMI of subjects via univariate and multivariate analyses. • A multivariate logistics regression model, the performance of which was analysed from a receiver operator characteristics curve, was applied to assess the predictive capacity of variables shown to be significant predictors of adverse pathological outcome. RESULTS: • Among our subjects, only 17 (1.7%) men had BMI ≥30 kg/m(2). After adjusting for various clinical variables, BMI (highest quartile vs others) was shown to be significantly associated with extracapsular extension of tumour (P= 0.014) and positive surgical margin (P= 0.019), but not with high pathological Gleason score (P= 0.912) and seminal vesicle invasion (P= 0.191). • Meanwhile, the addition of BMI to a multivariate model devised for preoperatively predicting extracapsular extension of tumour did not significantly increase predictive accuracy of the model (P= 0.319). On multivariate analysis, BMI was not shown to be a significant predictor of biochemical recurrence-free survival (P= 0.201). CONCLUSION: • Although higher BMI was significantly associated with extracapsular extension of tumour, BMI did not significantly enhance the ability to preoperatively predict extracapsular extension of tumour and was not significantly associated with PSA outcome or with other objective pathological outcomes in Korean men undergoing RP, who are generally leaner than their western counterparts.

Chronic kidney disease among men with lower urinary tract symptoms due to benign prostatic hyperplasia.

OBJECTIVE: To analyse potential association of various clinical characteristics of benign prostatic hyperplasia (BPH) with chronic kidney disease (CKD) among men presenting with lower urinary tract symptoms (LUTS) secondary to BPH of varying severity. PATIENTS AND METHODS: We reviewed the data of 2741 consecutive patients who presented to our clinic with LUTS secondary to BPH. For our analysis, CKD was defined by an elevated serum creatinine level or decreased estimated glomerular filtration rate (eGFR). Univariate and multivariate logistic regression analyses were used to address associations of CKD with various clinical characteristics. RESULTS: Of the 2741 patients, 161 (5.9%) were initially classified as having CKD (serum creatinine > or =133 micromol/L). In multivariate analysis, peak flow rate (P = 0.001) and a history of hypertension and/or diabetes (both P < 0.001) were significantly associated with CKD, whereas age, body mass index, prostate-specific antigen level, prostate volume, postvoid residual, or International Prostate Symptom Score (IPSS) were not. When individual symptoms from the IPSS were analysed, only weak stream (P = 0.041) and hesitancy (P = 0.048), both obstruction-related, were significantly associated with CKD status in age and comorbidity-adjusted analyses. The results of secondary analysis with CKD defined as an eGFR of <60 mL/min/1.73 m(2) were similar. CONCLUSION: Our results show that decreased peak flow rate and a history of hypertension and/or diabetes are significantly associated with CKD in men seeking management for LUTS from BPH of varying severity.

Prediction of Gleason score upgrading in low-risk prostate cancers diagnosed via multi (> or = 12)-core prostate biopsy.

OBJECTIVES: A paucity of data exists on actual pathology of the contemporary patients strictly categorized as having low-risk prostate cancer. We tried to identify useful preoperative predictors of Gleason score upgrading in patients who underwent radical retropubic prostatectomy (RRP) for low-risk prostate cancer diagnosed via multi-core prostate biopsy. METHODS: A total of 203 patients who underwent radical RRP for low-risk prostate cancer, as defined by D'Amico et al.'s classification (clinical stage < or = T2a, biopsy Gleason sum < or = 6, and PSA < or = 10 ng/ml), detected via multi (> or = 12)-core prostate biopsy were enrolled. We reviewed patients preoperative and pathological data. RESULTS: Among all subjects, 81 (39.9%) were upgraded to Gleason score > or = 7 after RRP, whereas no downgrading was observed. In multivariate analysis, only preoperative PSA level (P = 0.024) and number of positive cores (P = 0.027) were observed to be independent predictors of Gleason score upgrading following RRP. Also, Gleason core upgrading was observed to be significantly associated with extraprostatic extension of tumor (P < 0.001) and positive surgical margin (P = 0.002). CONCLUSIONS: A significant proportion of patients with low-risk prostate cancer as defined by D'Amico et al.'s classification diagnosed via multi-core prostate biopsy in contemporary period may have Gleason score upgrading following RRP. For patients with low-risk prostate cancer, preoperative PSA level and number of positive cores may be useful predictors of Gleason score upgrading, which was observed to significantly associated with other adverse pathologic features.

Korea Brain Initiative: Emerging Issues and Institutionalization of Neuroethics.

Neuroscience research has become a national priority for the Korean government. Korean scholars have dedicated interest in the societal ramifications of neurotechnologies; neuroethics is an integral component of the Korea Brain Initiative and to the formation of its growing neuroscience community.

Exogenous tumor necrosis factor-alpha rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn.

The proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is involved in the generation of inflammatory and neuropathic pain. This study investigated if TNF-alpha has any effect on spinal synaptic and/or sensory transmission by using whole-cell recordings of substantia gelatinosa (SG) neurons in transverse lumbar spinal cord slices of adult rats and by using behavioral tests. After intrathecal administration of TNF-alpha in adult rats, spontaneous hind paw withdrawal behavior and thermal hyperalgesia were rapidly induced (approximately 30 min), while mechanical allodynia slowly developed. Bath application of TNF-alpha (0.1-1 nM, 8 min) depressed peak amplitude of monosynaptic Adelta and C fiber-evoked excitatory postsynaptic currents (EPSCs) without changing in holding currents and input resistances, whereas this application generally potentiated polysynaptic Adelta fiber-evoked EPSCs. Moreover, the frequencies, but not the amplitudes, of spontaneous and miniature EPSCs and spontaneous inhibitory postsynaptic currents were significantly increased by bath-applied TNF-alpha in most of the SG neurons. The effects of TNF-alpha on Adelta/C fiber-evoked monosynaptic and polysynaptic or spontaneous EPSCs were significantly blocked by 5 microM TNF-alpha antagonist that inhibits TNF-alpha binding to its type 1 receptor (TNFR1). Because this study also found high protein expression of TNFR1 in the adult dorsal root ganglion and no change of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) induced whole-cell currents by TNF-alpha, we conclude that presynaptic TNFR1 at Adelta/C primary afferent terminals contributes to the rapid alteration of synaptic transmission in the spinal SG, and the development of abnormal pain hypersensitivity by exogenous TNF-alpha.

Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives.

Increasingly, national governments across the globe are prioritizing investments in neuroscience. Currently, seven active or in-development national-level brain research initiatives exist, spanning four continents. Engaging with the underlying values and ethical concerns that drive brain research across cultural and continental divides is critical to future research. Culture influences what kinds of science are supported and where science can be conducted through ethical frameworks and evaluations of risk. Neuroscientists and philosophers alike have found themselves together encountering perennial questions; these questions are engaged by the field of neuroethics, related to the nature of understanding the self and identity, the existence and meaning of free will, defining the role of reason in human behavior, and more. With this Perspective article, we aim to prioritize and advance to the foreground a list of neuroethics questions for neuroscientists operating in the context of these international brain initiatives.

Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells.

In the central nervous system (CNS), myelin formation and repair are regulated by oligodendrocyte (OL) lineage cells, which sense and integrate signals from their environment, including from other glial cells and the extracellular matrix (ECM). The signaling pathways that coordinate this complex communication, however, remain poorly understood. The adhesion G protein-coupled receptor ADGRG1 (also known as GPR56) is an evolutionarily conserved regulator of OL development in humans, mice, and zebrafish, although its activating ligand for OL lineage cells is unknown. Here, we report that microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OL precursor cells (OPCs) in the presence of the ECM protein laminin and that TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation. Signaling by TG2/laminin to ADGRG1 on OPCs additionally improves remyelination in two murine models of demyelination. These findings identify a novel glia-to-glia signaling pathway that promotes myelin formation and repair, and suggest new strategies to enhance remyelination.

Huntingtin is localized in the nucleus during preimplanatation embryo development in mice.

Huntington's disease (HD) is a dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the gene encoding huntingtin. Moreover, the nuclear targeting of mutant huntingtin increases cellular toxicity, whereas normal huntingtin resides mainly in the cytoplasm, and is associated with membranes or microtubules. Huntingtin is enriched in neurons and its expression is increased during neural development. The inactivation of the HD gene results in embryonic lethality before nervous system development. Thus, huntingtin is critical during early embryonic development. Nevertheless, the function of huntingtin at this stage is unknown, even the distribution of the protein has not been described. The present study was undertaken to elucidate the distribution of huntingtin during the early developmental period in the mouse embryo. At the preimplantation stage, huntingtin was detected in nuclei up to 2.5 days post coitum (dpc), but disappeared from nuclei during the blastocyst stage (3.5 dpc). Following this stage, huntingtin was mainly localized in the cytoplasm and co-localized with mitotic spindles. These data suggest that the nuclear targeting of normal huntingtin is required during early embryo development in mice.

Korea Brain Initiative: Integration and Control of Brain Functions.

This article introduces the history and the long-term goals of the Korea Brain Initiative, which is centered on deciphering the brain functions and mechanisms that mediate the integration and control of brain functions that underlie decision-making. The goal of this initiative is the mapping of a functional connectome with searchable, multi-dimensional, and information-integrated features. The project also includes the development of novel technologies and neuro-tools for integrated brain mapping. Beyond the scientific goals this grand endeavor will ultimately have socioeconomic ramifications that not only facilitate global collaboration in the neuroscience community, but also develop various brain science-related industrial and medical innovations.

ACT-PRESTO: Rapid and consistent tissue clearing and labeling method for 3-dimensional (3D) imaging.

Understanding the structural organization of organs and organisms at the cellular level is a fundamental challenge in biology. This task has been approached by reconstructing three-dimensional structure from images taken from serially sectioned tissues, which is not only labor-intensive and time-consuming but also error-prone. Recent advances in tissue clearing techniques allow visualization of cellular structures and neural networks inside of unsectioned whole tissues or the entire body. However, currently available protocols require long process times. Here, we present the rapid and highly reproducible ACT-PRESTO (active clarity technique-pressure related efficient and stable transfer of macromolecules into organs) method that clears tissues or the whole body within 1 day while preserving tissue architecture and protein-based signals derived from endogenous fluorescent proteins. Moreover, ACT-PRESTO is compatible with conventional immunolabeling methods and expedites antibody penetration into thick specimens by applying pressure. The speed and consistency of this method will allow high-content mapping and analysis of normal and pathological features in intact organs and bodies.

DRAGON: a member of the repulsive guidance molecule-related family of neuronal- and muscle-expressed membrane proteins is regulated by DRG11 and has neuronal adhesive properties.

DRG11, a transcription factor expressed in embryonic dorsal root ganglion (DRG) and dorsal horn neurons, has a role in the development of sensory circuits. We have used a genomic binding strategy to screen for the promoter region of genes regulated by DRG11. One gene with a promoter region binding to the DNA binding domain of DRG11 encodes a novel membrane-associated [glycosyl-phosphatidylinositol (GPI)-anchored] protein that we call DRAGON. DRAGON expression is transcriptionally regulated by DRG11, and it is coexpressed with DRG11 in embryonic DRG and spinal cord. DRAGON expression in these areas is reduced in DRG11 null mutants. DRAGON is expressed, however, in the neural tube before DRG11, and unlike DRG11 it is expressed in the brain and therefore must be regulated by other transcriptional regulatory elements. DRAGON shares high sequence homology with two other GPI-anchored membrane proteins: the mouse ortholog of chick repulsive guidance molecule (mRGM), which is expressed in the mouse nervous system in areas complementary to DRAGON, and DRAGON-like muscle (DL-M), the expression of which is restricted to skeletal and cardiac muscle. A comparative genomic analysis indicates that the family of RGM-related genes--mRGM, DRAGON, and DL-M--are highly conserved among mammals, zebrafish, chick, and Caenorhabditis elegans but not Drosophila. DRAGON, RGM, and DL-M mRNA expression in the zebrafish embryo is similar to that in the mouse. Neuronal cell adhesion assays indicate that DRAGON promotes and mRGM reduces adhesion of mouse DRG neurons. We show that DRAGON interacts with itself homophilically. The dynamic expression, ordered spatial localization, and adhesive properties of the RGM-related family of membrane-associated proteins are compatible with specific roles in development.

C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3beta expression.

The AICD (amyloid precursor protein [APP] intracellular domain) and C31, the caspase-cleaved C-terminal fragment of APP, have been found in the brains of patients with Alzheimer's disease (AD). Here, we demonstrate for the first time that the C-terminal fragments of APP (AICD [C57, C59] and C31) exert neurotoxicity on differentiated PC 12 cells and rat primary cortical neurons by inducing the expression of glycogen synthase kinase 3beta, forming a ternary complex with Fe65 and CP2/LSF/LBP1 in the nucleus, whereas deletion mutants and a point mutant with Y682G of the YENPTY domain, a Fe65 binding domain, do not. Moreover, expression of APP770 and Swedish mutant form of APP increased the levels of C-terminal fragments of APP (APP-CTs) in neuronal cells and also induced the up-regulation of glycogen synthase kinase-3beta at both the mRNA and the protein levels. In addition, we show that CP2/LSF/LBP1 binding site (nt +0 to approximately +10) in human glycogen synthase kinase 3beta promoter region is essential for the induction of the gene transcription by APP-CTs. The neurotoxicities induced by APP-CTs (AICD and C31) were accompanied by an increase in the active form of glycogen synthase kinase-3beta, and by the induction of tau phosphorylation and a reduction in nuclear beta-catenin levels, and led to apoptosis.