Scopus list of publications for December 17, 2023
Organ aging signatures in the plasma proteome track health and disease
(2023) Nature, 624 (7990), pp. 164-172.
Oh, H.S.-H.a b c , Rutledge, J.b c d , Nachun, D.e , Pálovics, R.b c f , Abiose, O.c f , Moran-Losada, P.b c f , Channappa, D.b c f , Urey, D.Y.b g , Kim, K.b c f , Sung, Y.J.h i , Wang, L.h i , Timsina, J.h i , Western, D.h i j , Liu, M.h i , Kohlfeld, P.h i , Budde, J.h i , Wilson, E.N.c f , Guen, Y.f k , Maurer, T.M.e , Haney, M.b c f , Yang, A.C.l m n , He, Z.f , Greicius, M.D.f , Andreasson, K.I.c f o , Sathyan, S.p , Weiss, E.F.q , Milman, S.p , Barzilai, N.p , Cruchaga, C.h i , Wagner, A.D.c r , Mormino, E.f , Lehallier, B.f , Henderson, V.W.c f s , Longo, F.M.c f , Montgomery, S.B.e t u , Wyss-Coray, T.b c f
a Graduate Program in Stem Cell and Regenerative Medicine, Stanford University, Stanford, CA, United States
b The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
c Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
d Graduate Program in Genetics, Stanford University, Stanford, CA, United States
e Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
f Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
g Department of Bioengineering, Stanford University School of Engineering, Stanford, CA, United States
h Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
i NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
j Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
k Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
l Departments of Neurology and Anatomy, University of California San Francisco, San Francisco, CA, United States
m Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, United States
n Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, United States
o Chan Zuckerberg Biohub, San Francisco, CA, United States
p Departments of Medicine and Genetics, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, United States
q Department of Neurology, Montefiore Medical Center, New York, NY, United States
r Department of Psychology, Stanford University, Stanford, CA, United States
s Department of Epidemiology and Population Health, Stanford University, Stanford, CA, United States
t Department of Genetics, Stanford University School of Medicine, Stanford, CA, United States
u Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, United States
Abstract
Animal studies show aging varies between individuals as well as between organs within an individual1–4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects. © 2023, The Author(s).
Funding details
T32AG047126
National Science FoundationNSF
National Institutes of HealthNIHP01AG003991, R01AG044546, RF1AG053303, RF1AG058501, RF1AG074007, U01AG058922
National Institute on AgingNIAAG044829, AG057909, AG061155, AG066206, P30AG066515, P50AG047366
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAZEN-22-848604
Milky Way Research FoundationMWRF
Nan Fung Life SciencesNFLS
Document Type: Article
Publication Stage: Final
Source: Scopus
Teaching NeuroImage: Severe Amyloid-Related Imaging Abnormalities after Anti-β-Amyloid Monoclonal Antibody Treatment
(2023) Neurology, 101 (23), pp. 1079-1080.
Bonomi, S.a , Samara, A.a , Balestra, N.a , Padalia, A.a , Benzinger, T.L.b c , Kang, P.a
a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, United States
c Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
A 74-year-old woman with mild Alzheimer disease joined a clinical trial of anti-amyloid-β therapy. Three weeks after receiving remternetug, a N3pH-Aβ monoclonal antibody, a scheduled brain MRI showed new periventricular and subcortical FLAIR hyperintensities (Figure, A) suggestive of mild amyloid-related imaging abnormalities (ARIA).1,2 Two weeks later, she was hospitalized for rapid cognitive and functional decline. Her admission examination was notable for severe disorientation, inattention, and global aphasia. Repeat MRI showed diffuse and confluent FLAIR hyperintensities consistent with progression to severe ARIA-edema/effusion (ARIA-E), but no hemosiderosis/microhemorrhages (ARIA-H) (Figure, B). She was treated with steroids and continued to have a gradual improvement in her cognition and language. A follow-up MRI 6 weeks later showed a marked reduction in FLAIR hyperintensities (Figure, C). In clinical trials, ARIA-E has often been observed to improve within 3-4 months.2 Early suspicion of ARIAs is essential for identifying and managing this adverse effect of anti-amyloid-β therapy. © American Academy of Neurology.
Document Type: Article
Publication Stage: Final
Source: Scopus
A common single nucleotide variant in the cytokine receptor-like factor-3 (CRLF3) gene causes neuronal deficits in human and mouse cells
(2023) Human Molecular Genetics, 32 (24), pp. 3342-3352.
Wilson, A.F.a , Barakat, R.a , Mu, R.a , Karush, L.L.a , Gao, Y.a , Hartigan, K.A.a , Chen, J.-K.a , Shu, H.b , Turner, T.N.c d , Maloney, S.E.b d , Mennerick, S.J.b , Gutmann, D.H.a , Anastasaki, C.a
a Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c Department of Genetics, Washington University School of Medicine, Box 8232, 660 South Euclid Avenue, St. Louis, MO 63110, United States
d Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, Box 8504, 660 South Euclid Avenue, St. Louis, MO 63110, United States
Abstract
Single nucleotide variants in the general population are common genomic alterations, where the majority are presumed to be silent polymorphisms without known clinical significance. Using human induced pluripotent stem cell (hiPSC) cerebral organoid modeling of the 1.4 megabase Neurofibromatosis type 1 (NF1) deletion syndrome, we previously discovered that the cytokine receptor-like factor-3 (CRLF3) gene, which is co-deleted with the NF1 gene, functions as a major regulator of neuronal maturation. Moreover, children with NF1 and the CRLF3L389P variant have greater autism burden, suggesting that this gene might be important for neurologic function. To explore the functional consequences of this variant, we generated CRLF3L389P-mutant hiPSC lines and Crlf3L389P-mutant genetically engineered mice. While this variant does not impair protein expression, brain structure, or mouse behavior, CRLF3L389P-mutant human cerebral organoids and mouse brains exhibit impaired neuronal maturation and dendrite formation. In addition, Crlf3L389P-mutant mouse neurons have reduced dendrite lengths and branching, without any axonal deficits. Moreover, Crlf3L389P-mutant mouse hippocampal neurons have decreased firing rates and synaptic current amplitudes relative to wild type controls. Taken together, these findings establish the CRLF3L389P variant as functionally deleterious and suggest that it may be a neurodevelopmental disease modifier. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Author Keywords
cerebral organoids; CRLF3; dendrites; neurodevelopment; neuron deficits; single nucleotide variant
Document Type: Article
Publication Stage: Final
Source: Scopus
Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1–TFEB pathway to Huntington’s disease neurodegeneration
(2023) Nature Aging, .
Lee, S.W.a g , Oh, Y.M.a g , Victor, M.B.b , Yang, Y.a , Chen, S.a , Strunilin, I.a , Dahiya, S.c , Dolle, R.E.d , Pak, S.C.e , Silverman, G.A.e , Perlmutter, D.H.e , Yoo, A.S.a f
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
g Department of Biomedical Sciences, Mercer University School of Medicine, Columbus, GA, United States
Abstract
Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs) in Huntington’s disease identified pathways involving RCAN1, a negative regulator of calcineurin. Notably, RCAN1 protein increased with age in reprogrammed MSNs as well as in human postmortem striatum and RCAN1 knockdown rescued patient-derived MSNs of Huntington’s disease from degeneration. RCAN1 knockdown enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, leading to TFEB’s nuclear localization by dephosphorylation. Furthermore, G2-115, an analog of glibenclamide with autophagy-enhancing activities, reduced the RCAN1–calcineurin interaction, phenocopying the effect of RCAN1 knockdown. Our results demonstrate that targeting RCAN1 genetically or pharmacologically can increase neuronal resilience in Huntington’s disease. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
Funding details
National Institute on AgingNIAR01AG078964, RF1AG056296
National Institute of Neurological Disorders and StrokeNINDSR01NS107488
Hereditary Disease FoundationHDF
CHDI FoundationCHDI
Cure Alzheimer’s FundCAF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Evaluation of gliovascular functions of AQP4 readthrough isoforms
(2023) Frontiers in Cellular Neuroscience, 17, art. no. 1272391, .
Mueller, S.M.a b , McFarland White, K.a b , Fass, S.B.a b , Chen, S.a b c , Shi, Z.d , Ge, X.c e , Engelbach, J.A.c e , Gaines, S.H.c , Bice, A.R.c , Vasek, M.J.a b , Garbow, J.R.c e , Culver, J.P.c f g h i , Martinez-Lozada, Z.j , Cohen-Salmon, M.k , Dougherty, J.D.a b e , Sapkota, D.d l
a Department of Genetics, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, United States
e Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, Saint Louis, MO, United States
f Department of Physics, Washington University in St. Louis, Saint Louis, MO, United States
g Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
h Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO, United States
i Imaging Science PhD Program, Washington University in St. Louis, Saint Louis, MO, United States
j Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
k Center for Interdisciplinary Research in Biology (CIRB), The National Centre for Scientific Research (CNRS), Collège de France, France
l Department of Neuroscience, University of Texas at Dallas, Richardson, TX, United States
Abstract
Aquaporin-4 (AQP4) is a water channel protein that links the astrocytic endfeet to the blood-brain barrier (BBB) and regulates water and potassium homeostasis in the brain, as well as the glymphatic clearance of waste products that would otherwise potentiate neurological diseases. Recently, translational readthrough was shown to generate a C-terminally extended variant of AQP4, known as AQP4x, which preferentially localizes around the BBB through interaction with the scaffolding protein α-syntrophin, and loss of AQP4x disrupts waste clearance from the brain. To investigate the function of AQP4x, we generated a novel AQP4 mouse line (AllX) to increase relative levels of the readthrough variant above the ~15% of AQP4 in the brain of wild-type (WT) mice. We validated the line and assessed characteristics that are affected by the presence of AQP4x, including AQP4 and α-syntrophin localization, integrity of the BBB, and neurovascular coupling. We compared AllXHom and AllXHet mice to WT and to previously characterized AQP4 NoXHet and NoXHom mice, which cannot produce AQP4x. An increased dose of AQP4x enhanced perivascular localization of α-syntrophin and AQP4, while total protein expression of the two was unchanged. However, at 100% readthrough, AQP4x localization and the formation of higher order complexes were disrupted. Electron microscopy showed that overall blood vessel morphology was unchanged except for an increased proportion of endothelial cells with budding vesicles in NoXHom mice, which may correspond to a leakier BBB or altered efflux that was identified in NoX mice using MRI. These data demonstrate that AQP4x plays a small but measurable role in maintaining BBB integrity as well as recruiting structural and functional support proteins to the blood vessel. This also establishes a new set of genetic tools for quantitatively modulating AQP4x levels. Copyright © 2023 Mueller, McFarland White, Fass, Chen, Shi, Ge, Engelbach, Gaines, Bice, Vasek, Garbow, Culver, Martinez-Lozada, Cohen-Salmon, Dougherty and Sapkota.
Author Keywords
AQP4; AQP4x; astrocyte; blood-brain barrier; glymphatic; readthrough
Funding details
National Institutes of HealthNIHR00AG061231, R01MH116999, R01NS102272
Children’s Hospital of PhiladelphiaCHOP
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
Intellectual and Developmental Disabilities Research CenterIDDRCP50HD103525
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
Document Type: Article
Publication Stage: Final
Source: Scopus
Multimodal Structural and Functional Characterization of Retinal Vasculopathy with Cerebral Leukoencephalopathy
(2023) Ophthalmology Retina, .
Wang, W.X., Shah, A.V., Bruck, B., Van Stavern, G., Rao, P.K., Apte, R.S.
John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States
Abstract
Objective: To describe and quantify the structural and functional consequences of retinal vasculopathy with cerebral leukoencephalopathy (RVCL) on the neurosensory retina. Design: Cross sectional descriptive study from December 2021 to December 2022. Participants: Retinal vasculopathy with cerebral leukoencephalopathy patients (n = 9, 18 eyes) recruited from the RVCL Research Center at Washington University in St. Louis. Methods: Retinal vasculopathy with cerebral leukoencephalopathy patients underwent comprehensive ophthalmological evaluation including OCT, OCT angiography (OCTA), ultrawidefield fundus imaging, retinal autofluorescence, dark adaptation, electroretinography (ERG), Goldmann kinetic perimetry, and fluorescein angiography (FA). Main Outcome Measures: Comprehensive characterization from various modalities including best-corrected visual acuity, central subfield thickness (μm) from OCT, foveal avascular zone (mm2) from OCTA, dark adaptation rod intercept (seconds), cone response in ERG, and presence or absence of vascular abnormalities, leakage, neovascularization, and nonperfusion on FA. Results: A total of 18 eyes from 9 individuals were included in this study. The best-corrected visual acuity ranged from 20/15 to 20/70. The mean central subfield thickness from OCT was 275.8 μm (range, 217–488 μm). The mean foveal avascular zone (FAZ) from OCTA was 0.65 (range, 0.18–1.76) mm2. On dark adaptometry, the mean time was 5.02 (range, 2.9–6.5) minutes, and 1 individual had impaired dark adaptation. Electroretinography demonstrated mild cone response impairment in 4 eyes. On FA, there was evidence of macular and peripheral capillary nonperfusion in 16 of 18 eyes and notable areas of vascular leakage and retinal edema in 5 of the 18 eyes. Conclusions: This study illustrates the phenotypic spectrum of disease and may be clinically valuable for aiding diagnosis, monitoring disease progression, and further elucidating the pathophysiology of RVCL to aid in the development of therapies. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. © 2023 American Academy of Ophthalmology
Author Keywords
FA; Multimodal characterization; OCT; OCT-A; Retinal vasculopathy with cerebral leukoencephalopathy
Funding details
Research to Prevent BlindnessRPB
Roche
Document Type: Article
Publication Stage: Article in Press
Source: Scopus