List of publications for the week of March 22, 2021
Loss of Quaking RNA binding protein disrupts the expression of genes associated with astrocyte maturation in mouse brain
(2021) Nature Communications, 12 (1), art. no. 1537, .
Sakers, K.a b , Liu, Y.a b , Llaci, L.c , Lee, S.M.a b , Vasek, M.J.a b , Rieger, M.A.a b , Brophy, S.a b , Tycksen, E.d , Lewis, R.e , Maloney, S.E.b , Dougherty, J.D.a b
a Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Division of Biomedical and Biological Sciences, Washington University School of Medicine, Saint Louis, MO, United States
d Genome Technology Access Center, McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, United States
e Hope Center, Washington University School of Medicine and Saint Louis University, Saint Louis, MO, United States
Abstract
Quaking RNA binding protein (QKI) is essential for oligodendrocyte development as myelination requires myelin basic protein mRNA regulation and localization by the cytoplasmic isoforms (e.g., QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we define the targets of QKI in the mouse brain via CLIPseq and we show that QKI-6 binds 3′UTRs of a subset of astrocytic mRNAs. Binding is also enriched near stop codons, mediated partially by QKI-binding motifs (QBMs), yet spreads to adjacent sequences. Using a viral approach for mosaic, astrocyte-specific gene mutation with simultaneous translating RNA sequencing (CRISPR-TRAPseq), we profile ribosome associated mRNA from QKI-null astrocytes in the mouse brain. This demonstrates a role for QKI in stabilizing CLIP-defined direct targets in astrocytes in vivo and further shows that QKI mutation disrupts the transcriptional changes for a discrete subset of genes associated with astrocyte maturation. © 2021, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Plasma amyloid‐beta levels in a pre‐symptomatic dutch‐type hereditary cerebral amyloid angiopathy pedigree: A cross‐sectional and longitudinal investigation
(2021) International Journal of Molecular Sciences, 22 (6), art. no. 2931, pp. 1-12.
Chatterjee, P.a b , Tegg, M.b , Pedrini, S.b , Fagan, A.M.c d , Xiong, C.d e , Singh, A.K.f , Taddei, K.b g , Gardener, S.b , Masters, C.L.h , Schofield, P.R.i j , Multhaup, G.k , Benzinger, T.L.S.d l , Morris, J.C.c d , Bateman, R.J.c d , Greenberg, S.M.m , van Buchem, M.A.n , Stoops, E.o , Vanderstichele, H.p , Teunissen, C.E.q , Hankey, G.J.r , Wermer, M.J.H.s , Sohrabi, H.R.a b g t u , Martins, R.N.a b g u v , the Dominantly Inherited Alzheimer Networkw
a Department of Biomedical Sciences, Macquarie University, North Ryde, NSW 2109, Australia
b School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
c Department of Neurology, Washington University, St. Louis, MO 63130, United States
d Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63130, United States
e Division of Biostatistics, Washington University, St. Louis, MO 63130, United States
f Macquarie Business School, Macquarie University, North Ryde, NSW 2109, Australia
g Australian Alzheimer’s Research Foundation, Nedlands, WA 6009, Australia
h The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia
i Neuroscience Research Australia, Sydney, NSW 2031, Australia
j School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
k Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada
l Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
m Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA 02114, United States
n Department of Radiology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
o ADx NeuroSciences, Gent, 9052, Belgium
p Biomarkable, Gent, 9000, Belgium
q Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Amsterdam, 1007 MB, Netherlands
r Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, WA 6009, Australia
s Department of Neurology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
t Centre for Healthy Ageing, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA 6150, Australia
u School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA 6009, Australia
v The KaRa Institute of Neurological Disease, Macquarie Park, NSW 2113, Australia
Abstract
Plasma amyloid‐beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre‐symptomatic Dutch‐type hereditary CAA (D‐CAA) mutation‐carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre‐symptomatic members of a D‐ CAA pedigree were assembled and followed up 3–4 years later (NC = 8;MC = 9). Plasma Aβ1‐40 and Aβ1‐42 were cross‐sectionally and longitudinally analysed at baseline (T1) and follow‐up (T2) and were found to be lower in MCs compared to NCs, cross‐sectionally after adjusting for covari-ates, at both T1(Aβ1‐40: p = 0.001; Aβ1‐42: p = 0.0004) and T2 (Aβ1‐40: p = 0.001; Aβ1‐42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1‐40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1‐42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre‐symptomatic CAA, however, further validation studies in larger sample sets are required. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Author Keywords
Amyloid‐beta; Blood biomarkers; Cerebral amyloid angiopathy; Early diagnosis; Hereditary cerebral haemorrhage with amyloidosis—Dutch type; Plasma amyloid‐beta; Single molecule array platform
Funding details
National Health and Medical Research CouncilNHMRCAPP1129627
National Institutes of HealthNIHU19AG032438
Document Type: Article
Publication Stage: Final
Source: Scopus
Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice
(2021) Frontiers in Behavioral Neuroscience, 15, art. no. 615798, .
Minakova, E.a , Sarafinovska, S.b c d , Mikati, M.O.c e f g h , Barclay, K.M.e f g h , McCullough, K.B.b c , Dougherty, J.D.b c i , Al-Hasani, R.e f g h , Maloney, S.E.c i
a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
b Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Medical Scientist Training Program, Washington University in St. Louis, St. Louis, MO, United States
e Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
f Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
g Washington University Pain Center, Washington University in St. Louis, St. Louis, MO, United States
h Center for Clinical Pharmacology, St. Louis College of Pharmacy, University of Health Sciences and Pharmacy, St. Louis, MO, United States
i Intellectual and Developmental Disabilities Research Center, Washington University In St. Louis, St. Louis, MO, United States
Abstract
Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids in utero goes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact of in utero and prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth, in utero oxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in utero Oxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in utero Veh) or biologically reared (prolonged Veh) controls. In utero Oxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits. © Copyright © 2021 Minakova, Sarafinovska, Mikati, Barclay, McCullough, Dougherty, Al-Hasani and Maloney.
Author Keywords
behavior; in utero; neonatal abstinence syndrome; opioid; oxycodone; post-natal
Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATSULITR002345
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50 HD103525
Washington University School of Medicine in St. Louis20-186-9770
Document Type: Article
Publication Stage: Final
Source: Scopus
Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults
(2021) Brain, Behavior, and Immunity, .
Albrecht, D.S.a , Sagare, A.b , Pachicano, M.b , Sweeney, M.D.b , Toga, A.a , Zlokovic, B.b , Chui, H.c , Joe, E.c , Schneider, L.c , Morris, J.C.d , Benzinger, T.d , Pa, J.a c
a Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States
b Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States
c Alzheimer Disease Research Center, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States
d Department of Neurology, Department of Radiology, and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults. Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [18F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions. Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships. Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate. © 2021
Author Keywords
Amyloid-β; Chemokine; Cytokine; Glial activation; Neuroinflammation; PET imaging; Tau
Funding details
National Institute on AgingNIAP01AG03991, P01AG052350, P50AG05681, R01AG054617, P01AG026276
Document Type: Article
Publication Stage: Article in Press
Source: Scopus