Hope Center member publications

Generation of a gene-corrected human isogenic iPSC line from an Alzheimer’s disease iPSC line carrying the London mutation in APP (V717I)
(2021) Stem Cell Research, 53, art. no. 102373, . 

Hernández, D.^a , Morgan Schlicht, S.^a , Daniszewski, M.^a , Karch, C.M.^b , Goate, A.M.^c , Pébay, A.^a d , Dominantly Inherited Alzheimer Network (DIAN)^e

^a Department of Anatomy and Physiology, the University of Melbourne, Parkville, VIC 3010, Australia
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States
^d Department of Surgery, Royal Melbourne Hospital, the University of Melbourne, Parkville, VIC 3010, Australia

Abstract
We report the genome-editing of an existing iPSC line carrying the London mutation in APP (V717I) into an iPSC line in which the pathogenic mutation was corrected. The resulting isogenic iPSC line maintained pluripotent stem cell morphology, a normal karyotype, expression of pluripotency markers and the ability to differentiate into the three germ-layers in vitro. © 2021 The Author(s)

Funding details
Japan Agency for Medical Research and DevelopmentAMED
National Institute on AgingNIA
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Japan Agency for Medical Research and DevelopmentAMED
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
National Health and Medical Research CouncilNHMRC1154389
Brain Foundation
University of MelbourneUNIMELB

Document Type: Article
Publication Stage: Final
Source: Scopus

A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome
(2021) Cell Reports, 35 (4), p. 109040.

Henderson, M.J.^a , Trychta, K.A.^b , Yang, S.-M.^a , Bäck, S.^b , Yasgar, A.^a , Wires, E.S.^b , Danchik, C.^a , Yan, X.^b , Yano, H.^b , Shi, L.^b , Wu, K.-J.^c , Wang, A.Q.^a , Tao, D.^a , Zahoránszky-Kőhalmi, G.^a , Hu, X.^a , Xu, X.^a , Maloney, D.^a , Zakharov, A.V.^a , Rai, G.^a , Urano, F.^d , Airavaara, M.^e , Gavrilova, O.^f , Jadhav, A.^a , Wang, Y.^c , Simeonov, A.^a , Harvey, B.K.^b 

^a National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
^b National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
^c Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan
^d Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University in St. Louis, St. Louis, MO 63110, USA
^e Neuroscience Center, HiLIFE & Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
^f National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States

Abstract
Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions. Published by Elsevier Inc.

Author Keywords
bromocriptine;  diabetes;  endoplasmic reticulum;  ER calcium;  ER proteome;  ER retention sequence;  ER stress;  exodosis;  SERCaMP;  stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

Hemodynamic and oxygen-metabolic responses of the awake mouse brain to hypercapnia revealed by multi-parametric photoacoustic microscopy
(2021) Journal of Cerebral Blood Flow and Metabolism, . 

Cao, R.^a , Tran, A.^b , Li, J.^c , Xu, Z.^a , Sun, N.^a d , Zuo, Z.^c , Hu, S.^a d

^a Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
^b Department of Biology, University of Virginia, Charlottesville, VA, United States
^c Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States
^d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
A widely used cerebrovascular stimulus and common pathophysiologic condition, hypercapnia is of great interest in brain research. However, it remains controversial how hypercapnia affects brain hemodynamics and energy metabolism. By using multi-parametric photoacoustic microscopy, the multifaceted responses of the awake mouse brain to different levels of hypercapnia are investigated. Our results show significant and vessel type-dependent increases of the vessel diameter and blood flow in response to the hypercapnic challenges, along with a decrease in oxygen extraction fraction due to elevated venous blood oxygenation. Interestingly, the increased blood flow and decreased oxygen extraction are not commensurate with each other, which leads to reduced cerebral oxygen metabolism. Further, time-lapse imaging over 2-hour chronic hypercapnic challenges reveals that the structural, functional, and metabolic changes induced by severe hypercapnia (10% CO2) are not only more pronounced but more enduring than those induced by mild hypercapnia (5% CO2), indicating that the extent of brain’s compensatory response to chronic hypercapnia is inversely related to the severity of the challenge. Offering quantitative, dynamic, and CO2 level-dependent insights into the hemodynamic and metabolic responses of the brain to hypercapnia, these findings might provide useful guidance to the application of hypercapnia in brain research. © The Author(s) 2021.

Author Keywords
hemodynamics;  hypercapnia;  oxygen metabolism;  Photoacoustic microscopy;  vascular response

Funding details
National Science FoundationNSF20,23,988
National Institutes of HealthNIHNS099261, NS099118
American Heart AssociationAHA15SDG25960005

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Soluble P-tau217 reflects amyloid and tau pathology and mediates the association of amyloid with tau
(2021) EMBO Molecular Medicine, . 

Mattsson-Carlgren, N.^a b c , Janelidze, S.^a , Bateman, R.J.^d , Smith, R.^a , Stomrud, E.^a e , Serrano, G.E.^f , Reiman, E.M.^f , Palmqvist, S.^a e , Dage, J.L.^g , Beach, T.G.^h , Hansson, O.^a d e

^a Clinical Memory Research Unit, Faculty of Medicine, Lund University, Lund, Sweden
^b Department of Neurology, Skåne University Hospital, Lund University, Lund, Sweden
^c Wallenberg Center for Molecular Medicine, Lund University, Lund, Sweden
^d Department of Neurology, Washington University School of Medicine, Saint-Louis, MO, United States
^e Memory Clinic, Skåne University Hospital, Malmö, Sweden
^f Banner Alzheimer’s Institute, Phoenix, AZ, United States
^g Eli Lilly and Company, IndianapolisIN, United States
^h Banner Sun Health Research Institute, Sun City, AZ, United States

Abstract
Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N = 88), both plaque and tangle density contributed independently to higher P-tau217, but P-tau217 was not elevated in patients with non-Alzheimer’s disease tauopathies (N = 9). Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N = 426), where β-amyloid and tau PET were independently associated with P-tau217. P-tau217 concentrations correlated with β-amyloid PET (but not tau PET) in early disease stages and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 concentration is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles. © 2021 The Authors. Published under the terms of the CC BY 4.0 license

Author Keywords
Alzheimer’s disease;  amyloid;  phosphorylated tau;  plasma;  tau

Funding details
VetenskapsrådetVR2016‐00906
AlzheimerfondenAF‐939932
Region Skåne
FO2019‐0326, FO2020‐0275
Knut och Alice Wallenbergs StiftelseNMC 2019‐2022, 2017‐0383
2020‐0314
Lunds Universitet
Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
1280/20
Marianne and Marcus Wallenberg FoundationMMW2015.0125
University Hospital FoundationUHF2020‐O000028
National Institute on AgingNIA
Michael J. Fox Foundation for Parkinson’s ResearchMJFF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Quantitative signal properties from standardized MRIs correlate with multiple sclerosis disability
(2021) Annals of Clinical and Translational Neurology, 8 (5), pp. 1096-1109. 

Brier, M.R.^a , Snyder, A.Z.^b , Tanenbaum, A.^a , Rudick, R.A.^c , Fisher, E.^c , Jones, S.^d , Shimony, J.S.^b , Cross, A.H.^a , Benzinger, T.L.S.^b , Naismith, R.T.^a

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Malinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Biogen, Cambridge, MA, United States
^d Imaging Institute, Cleveland Clinic, Cleveland, OH, United States

Abstract
Objective: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice. Methods: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures. Results: Intensity distribution metrics distinguished MS patients from control participants based on normalized non-lesional signal differences. This analysis revealed non-lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non-lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra-lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS-related disability. Interpretation: These results support the notion that non-lesional abnormalities correlate more strongly with MS-related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non-lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS-related disability. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Funding details
Biogen
National Institutes of HealthNIH1S10RR022984‐01A1, 1S10OD018091‐01
National Institutes of HealthNIHP30NS098577, 2R25NS090978‐06
Novartis
Biogen
Janssen Pharmaceuticals
Alzheimer’s AssociationAA
National Institutes of HealthNIH
Foundation for Barnes-Jewish Hospital
Avid Radiopharmaceuticals
Genentech
Roche
EMD Serono

Document Type: Article
Publication Stage: Final
Source: Scopus