Digital Commons Network^™

Hspb1 As A Novel Regulator Of Ferroptotic Cancer Cell Death, X. Sun, Z. Ou, M. Xie, R. Kang, Y. Fan, X. Niu, H. Wang, L. Cao, D. Tang

Journal Articles

Ferroptosis is an iron-dependent form of non-apoptotic cell death, but its molecular mechanism remains largely unknown. Here, we demonstrate that heat shock protein beta-1 (HSPB1) is a negative regulator of ferroptotic cancer cell death. Erastin, a specific ferroptosis-inducing compound, stimulates heat shock factor 1 (HSF1)-dependent HSPB1 expression in cancer cells. Knockdown of HSF1 and HSPB1 enhances erastin-induced ferroptosis, whereas heat shock pretreatment and overexpression of HSPB1 inhibits erastin-induced ferroptosis. Protein kinase C-mediated HSPB1 phosphorylation confers protection against ferroptosis by reducing iron-mediated production of lipid reactive oxygen species. Moreover, inhibition of the HSF1-HSPB1 pathway and HSPB1 phosphorylation increases the anticancer activity …

Full-Length Soluble Urokinase Plasminogen Activator Receptor Down-Modulates Nephrin Expression In Podocytes, M. Alfano, P. Cinque, G. Giusti, S. Proietti, M. Nebuloni, S. Danese, S. D'Alessio, M. Genua, P. C. Singhal, J. Mikulak, +5 Additional Authors

Journal Articles

Increased plasma level of soluble urokinase-type plasminogen activator receptor (suPAR) was associated recently with focal segmental glomerulosclerosis (FSGS). In addition, different clinical studies observed increased concentration of suPAR in various glomerular diseases and in other human pathologies with nephrotic syndromes such as HIV and Hantavirus infection, diabetes and cardiovascular disorders. Here, we show that suPAR induces nephrin down-modulation in human podocytes. This phenomenon is mediated only by full-length suPAR, is time-and dose-dependent and is associated with the suppression of Wilms' tumor 1 (WT-1) transcription factor expression. Moreover, an antagonist of alpha v beta 3 integrin RGDfv blocked suPAR-induced suppression of …

Hypersensitivity To Intravenous Iron: Classification, Terminology, Mechanisms And Management, J. Szebeni, S. Fishbane, M. Hedenus, S. Howaldt, F. Locatelli, S. Patni, D. Rampton, G. Weiss, J. Folkersen

Journal Articles

Intravenous (IV) iron therapy is widely used in iron deficiency anemias when oral iron is not tolerated or ineffective. Administration of IV iron is considered a safe procedure, but severe hypersensitivity reactions (HSRs) can occur at a very low frequency. Recently, new guidelines have been published by the European Medicines Agency (EMA) with the intention of making IV-iron therapy safer; however, the current protocols are still non-specific, non-evidence-based empiric measures which neglect the fact that the majority of IV-iron reactions are not Ig-E-mediated anaphylactic reactions. The field would benefit from new specific and effective methods for the prevention and treatment …

Geriatric Telemedicine: Background And Evidence For Telemedicine As A Way To Address The Challenges Of Geriatrics, Ronald C. Merrell

Surgery Publications

Objectives

The global population of elderly people is increasing at a remarkable rate, which may be expected to continue for some time. Older patients require more care, and with the current model of care delivery, the costs may be expected to rise, although higher cost is unsustainable. For this reason, a new pattern of practice is needed. Telemedicine will be presented as a highly effective and necessary tool in geriatrics.

Methods

This review will present some of the background and evidence for telemedicine as a way to address the challenges of geriatrics through geriatric telemedicine. Some of the evidence for …

Addition Of Interleukin-21 For Expansion Of T-Cells For Adoptive Immunotherapy Of Murine Melanoma, Christine Kathryn Zoon, Wen Wan, Laura Graham, Harry D. Bear

Surgery Publications

We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Naïve T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and …

Zipline-Related Injuries Treated In Us Eds, 1997-2012, Rachel M. Billock, Jonathan J. Anderegg, Tracy J. Mehan, Thiphalak Chounthirath, Gary A. Smith

Faculty Publications - Department of Communication and Cinematic Arts

Purpose

To investigate the epidemiology of zipline-related injuries in the United States.

Basic Procedures

The National Electronic Injury Surveillance System database was used to examine non-fatal zipline-related injuries treated in US emergency departments (EDs) from 1997 through 2012. Sample weights were applied to calculate national estimates.

Main Findings

From 1997 through 2012, an estimated 16850 (95% CI, 13188-20512) zipline-related injuries were treated in US EDs. The annual injury rate per 1 million population increased by 52.3% from 7.64 (95% CI, 4.86-10.42) injuries in 2009 (the first year with a stable annual estimate) to 11.64 (95% CI, 7.83-15.45) injuries in 2012. …

Cancer Stem Cells In The Screening Of Anticancer Drugs For Central Nervous System Tumors, Sarah Elizabeth Daron-Mathis

Theses, Dissertations and Capstones

There is a growing need (in the medical field) to design personalized therapy for cancer patients. Decades of cancer research have found no silver bullet that can cure all or even most patients. This study evaluated four patients affected by central nervous system (CNS) tumors (Ependymoma and Glioblastoma), and found that tumors with the same histology had unique responses to treatment. Each sample presented different levels of heterogeneity in expressed biomarkers and responded to drugs at varying levels.

Oncologists conventionally treat cancer patients with drugs tested in large clinical trials. However, often patients do not experience positive outcomes following treatments …

Investigation Of Ultrasound Targeted Microbubbles As A Therapeutic Gene Delivery System For Prostate Cancer, Rounak Paramjeet Nande

Theses, Dissertations and Capstones

A major challenge for effective gene therapy is systemic delivery of viruses carrying therapeutic genes into affected tissue. The immunogenic nature of human adenoviruses (Ads) limits their use for intratumoral (IT) injection in gene therapy. Ads transfection is further hampered by the fluctuating presence of Coxsackie and Adenovirus Receptor (CAR) and integrins on the cells’ surface. To circumvent these limitations we developed a novel approach wherein Ads are encapsulated inside the shell of lyophilized, lipid-encapsulated, perfluorocarbon microbubbles (MBs)/ultrasound (US) contrast agents, which act as delivery vehicles for a sitespecific gene transfer system.

We performed infection studies with Ad.GFP (Green Fluorescent …

Oncology Section Edge Task Force On Prostate Cancer Outcomes: A Systematic Review Of Clinical Measures Of Strength And Muscular Endurance, Mary Insana Fisher, Claire Davies, Genevieve Colon, Hannah Geyer, Lucinda Pfalzer

Physical Therapy Faculty Publications

Background: Strength deficits are a common morbidity following treatment for prostate cancer. Accurate assessment of strength and muscular endurance following prostate cancer treatments is essential to identify deficits and plan rehabilitation.

Purpose: To identify strength and muscular endurance outcome measures that possess strong psychometric properties and are clinically useful for examination of men treated for prostate cancer.

Methods: Multiple electronic databases were searched for articles published after 1995. Studies of tools used to assess strength and muscular endurance were included if they reported psychometric properties, were clinically feasible methods, performed on adults, and published in the English language. Each outcome …

Educational Technology Improves Ecg Interpretation Of Acute Myocardial Infarction For Medical Students And Emergency Medicine Residents, Ali Pourmand, Mary Tanski, Steven Davis, Hamid A. Shokoohi, Raymond Lucas, Fareen Zaver

Emergency Medicine Faculty Publications

Introduction: Asynchronous online training has become an increasingly popular educational format in the new era of technology-based professional development. We sought to evaluate the impact of an online asynchronous training module on the ability of medical students and emergency medicine (EM) residents to detect electrocardiogram (ECG) abnormalities of an acute myocardial infarction (AMI).

Methods: We developed an online ECG training and testing module on AMI, with emphasis on recognizing ST elevation myocardial infarction (MI) and early activation of cardiac catheterization resources. Study participants included senior medical students and EM residents at all postgraduate levels rotating in our emergency department (ED). …

Improving Anatomical Knowledge Through Interactive Modules On The Ob/Gyn Clinical Clerkship, Artin Galoosian, Jill A. Krapf, Kirsten Brown, Gisela Butera, Ellen F. Goldman, Rosalyn A. Jurjus

Anatomy and Regenerative Biology Faculty Posters and Presentations

The goal of this study is to evaluate the impact of a newly designed interactive method of teaching clinically relevant anatomy to medical students on the OB/GYN clerkship. A 20-question multiple-choice exam was administered to 143 consenting third-year medical students at the beginning and end of each OB/GYN rotation. Students participated in a skills lab with preparatory e-modules that linked anatomy to clinical applications during each rotation. Topics included perineal muscle anatomy (laceration), anterior abdominal wall anatomy (cesarean section), vulvovaginal and uterine anatomy (IUD), and pelvic organ, vasculature, and neural anatomy (hysterectomy). Mean scores improved significantly after the nesting of …

Improving Newborn Care Practices Through Home Visits: Lessons From Malawi, Nepal, Bangladesh, And Uganda., Deborah Sitrin, Tanya Guenther, Peter Waiswa, Sarah Namutamba, Gertrude Namazzi, Srijana Sharma, K. C. Ashish, Sayed Rubayet, Subrata Bhadra, Reuben Ligowe, Emmanuel Chimbalanga, Elizabeth Sewell, Kate Kerber, Allisyn Moran

Pediatrics Faculty Publications

Background: Nearly all newborn deaths occur in low- or middle-income countries. Many of these deaths could be prevented through promotion and provision of newborn care practices such as thermal care, early and exclusive breastfeeding, and hygienic cord care. Home visit programmes promoting these practices were piloted in Malawi, Nepal, Bangladesh, and Uganda.

Objective: This study assessed changes in selected newborn care practices over time in pilot programme areas in four countries and evaluated whether women who received home visits during pregnancy were more likely to report use of three key practices.

Design: Using data from cross-sectional surveys …

Beyond Cd19: Opportunities For Future Development Of Targeted Immunotherapy In Pediatric Relapsed-Refractory Acute Leukemia., Haneen Shalabi, Anne Angiolillo, Terry J Fry

Pediatrics Faculty Publications

Chimeric antigen receptor (CAR) T cell therapy has been used as a targeted approach in cancer therapy. Relapsed and refractory acute leukemia in pediatrics has been difficult to treat with conventional therapy due to dose-limiting toxicities. With the recent success of CD 19 CAR in pediatric patients with B cell acute lymphoblastic leukemia (ALL), this mode of therapy has become a very attractive option for these patients with high-risk disease. In this review, we will discuss current treatment paradigms of pediatric acute leukemia and potential therapeutic targets for additional high-risk populations, including T cell ALL, AML, and infant ALL.

Genetic And Informatic Analyses Implicate Kif12 As A Candidate Gene Within The Mpkd2 Locus That Modulates Renal Cystic Disease Severity In The Cys1cpk Mouse., Michal Mrug, Juling Zhou, Chaozhe Yang, Bruce J Aronow, Xiangqin Cui, Trenton R Schoeb, Gene P Siegal, Bradley K Yoder, Lisa M. Guay-Woodford

Pediatrics Faculty Publications

We have previously mapped the interval on Chromosome 4 for a major polycystic kidney disease modifier (Mpkd) of the B6(Cg)-Cys1cpk/J mouse model of recessive polycystic kidney disease (PKD). Informatic analyses predicted that this interval contains at least three individual renal cystic disease severity-modulating loci (Mpkd1-3). In the current study, we provide further validation of these predicted effects using a congenic mouse line carrying the entire CAST/EiJ (CAST)-derived Mpkd1-3 interval on the C57BL/6J background. We have also generated a derivative congenic line with a refined CAST-derived Mpkd1-2 interval and demonstrated its dominantly-acting disease-modulating effects (e.g., 4.2-fold increase in total cyst area; …

Mllt1 Yeats Domain Mutations In Clinically Distinctive Favourable Histology Wilms Tumours., Elizabeth J Perlman, Samantha Gadd, Stefan T Arold, Anand Radhakrishnan, Daniela S Gerhard, Jeffrey S. Dome, +19 Additional Authors

Pediatrics Faculty Publications

Wilms tumour is an embryonal tumour of childhood that closely resembles the developing kidney. Genomic changes responsible for the development of the majority of Wilms tumours remain largely unknown. Here we identify recurrent mutations within Wilms tumours that involve the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Moreover, MLLT1-mutant tumours show an increase in MYC gene expression and HOX dysregulation. Patients with MLLT1-mutant tumours present at a younger age and have a high prevalence of precursor intralobar …

Liver Sinusoid On A Chip: Long-Term Layered Co-Culture Of Primary Rat Hepatocytes And Endothelial Cells In Microfluidic Platforms, Young Bok (Abraham) Kang, Temitope R. Sodunke, Jason Lamontagne, Joseph Cirillo, Caroline Rajiv, Michael J. Bouchard, Moses Noh

Faculty Publications - Biomedical, Mechanical, and Civil Engineering

We describe the generation of microfluidic platforms for the co-culture of primary hepatocytes and endothelial cells; these platforms mimic the architecture of a liver sinusoid. This paper describes a progressional study of creating such a liver sinusoid on a chip system. Primary rat hepatocytes (PRHs) were co-cultured with primary or established endothelial cells in layers in single and dual microchannel configurations with or without continuous perfusion. Cell viability and maintenance of hepatocyte functions were monitored and compared for diverse experimental conditions. When primary rat hepatocytes were co-cultured with immortalized bovine aortic endothelial cells (BAECs) in a dual microchannel with continuous …

Caregiver Perceptions Of Their Influence On Cancer Treatment Decision Making: Intersections Of Language, Identity, And Illness, Janice L. Krieger, Angela L. Palmer-Wackerly, Jessica L. Krok-Schoen, Phokeng M. Dailey, Julianne C. Wojno, Nancy Schoenberg, Electra D. Paskett, Mark Dignan

Department of Communication Studies: Faculty Publications

Serious illness of a loved one can disrupt a caregiver’s sense of self and relationships. We examined the language caregivers use to describe the cancer treatment decision making of a loved one to understand how caregivers frame their own identity relative to a patient’s illness. We analyzed transcripts from in-depth interviews conducted with caregivers (N = 58) of cancer patients to examine the intersection among language, identity, and illness. Caregivers with a patient-level personal identity frame used phrases such as their body, their decision. Caregivers with a relational identity frame used plural pronouns such as we or our when describing …

Serum Amyloid A Stimulates Pkr Expression And Hmgb1 Release Possibly Through Tlr4/Rage Receptors, W. Li, S. Zhu, J. Li, J. D'Amore, J. D'Angelo, H. Yang, P. Wang, K. J. Tracey, H. Wang

Journal Articles

Serum amyloid A proteins (SAAs) have been suggested as surrogate markers of sepsis, but their pathogenic roles remain poorly elucidated. Here we provide evidence to support a possible role of SAA as a pathogenic mediator of lethal sepsis. In a subset of septic patients whose serum HMGB1 levels paralleled with the clinical scores, some anti-HMGB1 antibodies detected a 12 kDa protein belonging to the SAA family. In contrast to the most abundant SAA1, human SAA induced PKR expression and HMGB1 release in the wild-type, but not TLR4/RAGE-deficient, macrophages. Pharmacological inhibition of PKR phosphorylation blocked SAA-induced HMGB1 release, suggesting an important …

Platelet-Rich Plasma And Other Cellular Strategies In Orthopedic Surgery, P. N. Williams, G. Moran, J. P. Bradley, N. S. Elattrache, J. S. Dines

Journal Articles

The use of biologics in the treatment of musculoskeletal disease has become increasingly more common as research studies continue to provide further elucidation of their mechanisms in healing. Platelet-rich plasma, patches, growth factors, and stem cells are among the many biologics under active investigation and have varying levels of success in augmenting surgical or nonoperative interventions. However, the limitations of these treatments exist, and clear guidelines for their indications and application have yet to be established. Well-designed clinical trials will help determine the appropriate future use of biologics to ensure consistent outcomes.

Integrating Biodegradable 3-Dimensional-Printing Into Tracheal Reconstruction, T. Goldstein, L. Smith, B. Smith, D. Grande, D. Zeltsman

Journal Articles

No abstract provided.

Comorbid Profile Rather Than Age Determines Hip Fracture Mortality In A Nonagenarian Population, A. Graver, S. Merwin, L. Collins, N. Kohn, A. Goldman

Journal Articles

BACKGROUND: In light of poor outcomes with nonoperative management of hip fractures, orthopedic surgeons are faced with difficult decisions about which patients are too ill or too old for surgical treatment. QUESTIONS/PURPOSES: This study sought to investigate if patients over 90 years had different preoperative laboratory, clinical, and injury characteristics than younger patients with the same injury. We compared our cohort with previously published data. We wished to identify if there were pre-injury risk factors associated with 30-day mortality, which could be modified to enhance postoperative outcomes. METHODS: This is a retrospective review of 198 operatively managed hip fractures in …

Stress Induces The Danger-Associated Molecular Pattern Hmgb-1 In The Hippocampus Of Male Sprague Dawley Rats: A Priming Stimulus Of Microglia And The Nlrp3 Inflammasome, M. D. Weber, M. G. Frank, K. J. Tracey, L. R. Watkins, S. F. Maier

Journal Articles

Exposure to acute and chronic stressors sensitizes the proinflammatory response of microglia to a subsequent immune challenge. However, the proximal signal by which stressors prime microglia remains unclear. Here, high mobility group box-1 (HMGB-1) protein was explored as a potential mediator of stress-induced microglial priming and whether HMGB-1 does so via the nucleotide-binding domain, leucine-rich repeat, pyrin domain containing protein 3 (NLRP3) inflammasome. Exposure to 100 inescapable tail shocks (ISs) increased HMGB-1 and NLRP3 protein in the hippocampus and led isolated microglia to release HMGB-1 ex vivo. To determine whether HMGB-1 signaling is necessary for stress-induced sensitization of microglia, the …

Galantamine Attenuates Type 1 Diabetes And Inhibits Anti-Insulin Antibodies In Non-Obese Diabetic Mice, W. M. Hanes, P. S. Olofsson, K. Kwan, L. K. Hudson, S. S. Chavan, V. A. Pavlov, K. J. Tracey

Journal Articles

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic beta cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin …

A Unifying Principle Underlying The Extracellular Field Potential Spectral Responses In The Human Cortex, E. Podvalny, N. Noy, M. Harel, S. Bickel, G. Chechik, C. E. Schroeder, A. D. Mehta, M. Tsodyks, R. Malach

Journal Articles

Electrophysiological mass potentials show complex spectral changes upon neuronal activation. However, it is unknown to what extent these complex band-limited changes are interrelated or, alternatively, reflect separate neuronal processes. To address this question, intracranial electrocorticograms (ECoG) responses were recorded in patients engaged in visuomotor tasks. We found that in the 10- to 100-Hz frequency range there was a significant reduction in the exponent chi of the 1/f(chi) component of the spectrum associated with neuronal activation. In a minority of electrodes showing particularly high activations the exponent reduction was associated with specific band-limited power modulations: emergence of a high gamma (80-100 …

Vascular Smooth Muscle Cells Contribute To Apol1-Induced Podocyte Injury In Hiv Milieu, X. Lan, H. Wen, M. A. Saleem, J. Mikulak, A. Malhotra, K. Skorecki, P. C. Singhal

Journal Articles

Clinical reports have demonstrated that higher rates of non-diabetic glomerulosclerosis in African Americans can be attributed to two coding sequence variants (G1 and G2) in the APOL1 gene; however, the underlying mechanism is still unknown. Kidney biopsy data suggest enhanced expression of APOL1/APOL1 variants (Vs) in smooth muscle cells (SMCs) of renal vasculature. Since APOL1 is a secretory protein of relatively low molecular weight (41kDa), SMCs may be a contributory endocrine/paracrine source of APOL1 wild type (WT)/APOL1Vs in the glomerular capillary perfusate percolating podocytes. In the present study, we tested the hypothesis that an HIV milieu stimulated secretion of APOL1 …

Epigenetic Modulation Of Human Podocyte Vitamin D Receptor In Hiv Milieu, N. Chandel, K. S. Ayasolla, X. Lan, M. Sultana-Syed, A. Chawla, R. Lederman, V. Vethantham, M. A. Saleem, A. Malhotra, P. C. Singhal, +1 Additional Author

Journal Articles

HIV (human immunodeficiency virus) has been reported to induce podocyte injury through down regulation of vitamin D receptor (VDR) and activation of renin angiotensin system; however, the involved mechanism is not clear. Since HIV has been reported to modulate gene expression via epigenetic phenomena, we asked whether epigenetic factors contribute to down regulation of VDR. Kidney cells in HIV transgenic mice and HIV-infected podocytes (HIV/HPs) displayed enhanced expression of SNAIL, a repressor of VDR. To elucidate the mechanism, we studied the effect of HIV on expression of molecules involved in SNAIL repressor complex formation and demonstrated that HIV enhances expression …

Image Artifacts In Optical Coherence Tomography Angiography, R. F. Spaide, J. G. Fujimoto, N. K. Waheed

Journal Articles

PURPOSE: To describe image artifacts of optical coherence tomography (OCT) angiography and their underlying causative mechanisms. To establish a common vocabulary for the artifacts observed. METHODS: The methods by which OCT angiography images are acquired, generated, and displayed are reviewed as are the mechanisms by which each or all of these methods can produce extraneous image information. A common set of terminology is proposed and used. RESULTS: Optical coherence tomography angiography uses motion contrast to image blood flow and thereby images the vasculature without the need for a contrast agent. Artifacts are very common and can arise from the OCT …

Effects Of Wharton's Jelly-Derived Mesenchymal Stem Cells On Neonatal Neutrophils, I. Khan, L. Zhang, M. Mohammed, F. E. Archer, J. Abukharmah, Z. Yuan, S. S. Rizvi, M. G. Melek, B. Weinberger, A. M. Vetrano, +2 Additional Authors

Journal Articles

BACKGROUND: Mesenchymal stem cells (MSCs) have been proposed as autologous therapy for inflammatory diseases in neonates. MSCs from umbilical cord Wharton's jelly (WJ-MSCs) are accessible, with high proliferative capacity. The effects of WJ-MSCs on neutrophil activity in neonates are not known. We compared the effects of WJ-MSCs on apoptosis and the expression of inflammatory, oxidant, and antioxidant mediators in adult and neonatal neutrophils. METHODS: WJ-MSCs were isolated, and their purity and function were confirmed by flow cytometry. Neutrophils were isolated from cord and adult blood by density centrifugation. The effects of neutrophil/WJ-MSC co-culture on apoptosis and gene and protein expression …

Assessing The Associations Of Sodium Intake With Long-Term All-Cause And Cardiovascular Mortality In A Hypertensive Cohort, P. Singer, H. Cohen, M. Alderman

Journal Articles

BACKGROUND: Although higher sodium intake is known to increase blood pressure, its association with cardiovascular mortality is less established. We examined the association of baseline sodium intake in a hypertensive cohort with all-cause and cardiovascular mortality over a mean follow-up of 18.6 years. METHODS: Three thousand five hundred five subjects were participants in a worksite hypertension program. Sodium intake was estimated by 24-hour urine excretion. Mortality data were obtained from the U.S. National Death Index. Unadjusted and multivariable-adjusted associations between sodium quartiles (quartile I (QI) to quartile IV (QIV)) and mortality were assessed using Cox models. RESULTS: Estimated mean +/- …

Calhm1 Ion Channel Elicits Amyloid-Beta Clearance By Insulin-Degrading Enzyme In Cell Lines And In Vivo In The Mouse Brain, V. Vingtdeux, P. Chandakkar, H. Zhao, L. Blanc, S. Ruiz, P. Marambaud

Journal Articles

Alzheimer's disease is characterized by amyloid-beta (Abeta) peptide accumulation in the brain. CALHM1, a cell-surface Ca(2+) channel expressed in brain neurons, has anti-amyloidogenic properties in cell cultures. Here, we show that CALHM1 controls Abeta levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of Abeta clearance. Using pharmacological and genetic approaches in cell lines, we found that CALHM1 ion permeability and extracellular Ca(2+) were required for the Abeta-lowering effect of CALHM1. Abeta level reduction by CALHM1 could be explained by an increase in extracellular Abeta degradation by insulin-degrading enzyme (IDE), extracellular secretion of which was …