Hope Center Member Publications

List of publications for August 3, 2022

Acrylamide inhibits long-term potentiation and learning involving microglia and pro-inflammatory signaling” (2022) Scientific Reports

Acrylamide inhibits long-term potentiation and learning involving microglia and pro-inflammatory signaling
(2022) Scientific Reports, 12 (1), art. no. 12429, . 

Izumi, Y.a b , Fujii, C.a , O’Dell, K.A.a b , Zorumski, C.F.a b

a Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary exposure to acrylamide could impair cognitive function because of its neurotoxicity. Using rat hippocampal slices, we tested whether acrylamide alters induction of long-term potentiation (LTP), a cellular model of learning and memory. We hypothesized that acrylamide impairs cognitive function via activation of pro-inflammatory cytokines because robust upregulation of NLRP3 inflammasome has been reported. Although acrylamide up to 3 mM did not alter basal synaptic transmission, incubation with 10 μM or acute administration of 100 μM acrylamide inhibited induction of LTP. Inhibitors of toll-like receptor 4 (TLR4), and minocycline, an inhibitor of microglial activation, overcame the effects of acrylamide on LTP induction. Furthermore, we observed that acrylamide failed to inhibit LTP after administration of MCC950, an inhibitor of NLRP3, or in the presence of Interleukin-1 receptor antagonist (IL-1Ra). We also found that in vivo acrylamide injection transiently impaired body weight gain and impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by MCC950. These results indicate that cognitive impairment by acrylamide is mediated by mechanisms involving microglia and release of cytokines via NLRP3 activation. © 2022, The Author(s).

Funding details
Banting Research FoundationBRF
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing” (2022) Pain

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing
(2022) Pain, 163 (8), pp. 1603-1621. 

Slivicki, R.A.a , Yi, J.a b , Brings, V.E.a , Huynh, P.N.a , Gereau, R.W.a c d

a Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
b Neuroscience Graduate Program, Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neuroscience, Washington University, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Activation of cannabinoid receptor type 1 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance, and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB1receptors to circumvent central CB1-related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB1-preferring agonist CB-13 on nociception and central CB1-related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB1-receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse dorsal root ganglion neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E2, providing potential mechanistic explanations for the analgesic actions of peripheral CB1receptor activation. With acute dosing, phenotypes associated with central CB1receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED50for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB1receptor dependence, even at a dose that did not produce central CB1-receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB1receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB1receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
Cannabinoid;  CB-13;  CB1;  Hyperexcitability;  Pain;  Peripherally restricted;  PGE2;  TRPV1

Funding details
National Institute on Drug AbuseNIDAF32 DA051160
National Institute of General Medical SciencesNIGMST32 GM108539
National Institute of Neurological Disorders and StrokeNINDSR01 NS042595, R34 NS126036
American Heart AssociationAHA
Washington University in St. LouisWUSTL

Document Type: Article
Publication Stage: Final
Source: Scopus

Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine” (2022) Science Advances

Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine
(2022) Science Advances, 8 (29), p. eabo3625. 

Yang, N.-D.a , Kanyo, R.b , Zhao, L.a , Li, J.b , Kang, P.W.a , Dou, A.K.a , White, K.M.a , Shi, J.a , Nerbonne, J.M.c , Kurata, H.T.b , Cui, J.a

a Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA
b Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
c Departments of Developmental Biology and Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA

KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening. We identified some epilepsy-linked mutations in KCNQ2 and KCNQ3 that disrupt E-M coupling. The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished by a mutation disrupting E-M coupling, suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.

Document Type: Article
Publication Stage: Final
Source: Scopus

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease” (2022) Nature Aging

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease
(2022) Nature Aging, 2 (7), pp. 616-634. Cited 1 time.

Jiang, Y.a b , Zhou, X.a b c , Wong, H.Y.a b , Ouyang, L.a b , Ip, F.C.F.a b c , Chau, V.M.N.a b , Lau, S.-F.a b , Wu, W.a b , Wong, D.Y.K.a b , Seo, H.a , Fu, W.-Y.a b , Lai, N.C.H.a b , Chen, Y.a c d , Chen, Y.a c d , Tong, E.P.S.a b , Weiner, M.W.q , Aisen, P.r , Petersen, R.s , Jack, C.R.s , Jagust, W.t , Trojanowski, J.Q.u , Toga, A.W.v , Beckett, L.w , Green, R.C.x , Saykin, A.J.y , Morris, J.z , Shaw, L.M.u , Khachaturian, Z.w aa , Sorensen, G.ab , Kuller, , Raichle, M.z , Paul, , Davies, , Fillit, , Hefti, , Holtzman, D.z , Mesulam, M.M.ah , Potter, , Snyder, P.aj , Schwartz, A.ak , Montine, , Thomas, , Donohue, , Walter, , Gessert, , Sather, , Jiminez, , Harvey, D.w , Bernstein, M.s , Thompson, , Schuff, N.q w , Borowski, B.s , Gunter, J.s , Senjem, M.s , Vemuri, P.s , Jones, D.s , Kantarci, K.s , Ward, C.s , Koeppe, , Foster, , Reiman, E.M.ap , Chen, K.ap , Mathis, , Landau, S.t , Cairns, N.J.z , Householder, E.z , Taylor-Reinwald, L.z , Lee, V.u , Korecka, M.u , Figurski, M.u , Crawford, K.v , Neu, S.v , Foroud, T.M.y , Potkin, , Shen, L.y , Faber, K.y , Kim, S.y , Nho, K.y , Thal, L.r , Buckholtz, , Albert, , Frank, , Hsiao, , Kaye, , Quinn, , Lind, , Carter, , Dolen, , Schneider, L.S.v , Pawluczyk, S.v , Beccera, M.v , Teodoro, L.v , Spann, B.M.v , Brewer, J.r , Vanderswag, H.r , Fleisher, A.r ap , Heidebrink, , Lord, , Mason, S.S.s , Albers, C.S.s , Knopman, D.s , Johnson, K.s , Doody, R.S.av , Villanueva-Meyer, J.av , Chowdhury, M.av , Rountree, S.av , Dang, M.av , Stern, Y.av , Honig, L.S.av , Bell, K.L.av , Ances, B.z , Carroll, M.z , Leon, S.z , Mintun, M.A.z , Schneider, S.z , Oliver, A.z , Marson, , Griffith, , Clark, , Geldmacher, , Brockington, , Roberson, , Grossman, , Mitsis, , de Toledo-Morrell, L.ay , Shah, R.C.ay , Duara, , Varon, , Greig, , Roberts, , Onyike, , D’Agostino, , Kielb, , Galvin, , Cerbone, , Michel, , Rusinek, , de Leon, , Glodzik, , De Santi, , Doraiswamy, , Petrella, , Wong, , Arnold, S.E.u , Karlawish, J.H.u , Wolk, D.u , Smith, C.D.bc , Jicha, G.bc , Hardy, P.bc , Sinha, P.bc , Oates, E.bc , Conrad, G.bc , Lopez, , Oakley, , Simpson, , Porsteinsson, , Goldstein, , Martin, , Makino, , Ismail, , Brand, , Mulnard, , Thai, , McAdams-Ortiz, , Womack, , Mathews, , Quiceno, , Diaz-Arrastia, , King, , Weiner, , Martin-Cook, , DeVous, , Levey, , Lah, , Cellar, , Burns, , Anderson, , Swerdlow, , Apostolova, , Tingus, , Woo, , Silverman, , Lu, , Bartzokis, , Graff-Radford, , Parfitt, , Kendall, , Johnson, , Farlow, M.R.y , Hake, A.M.y , Matthews, B.R.y , Herring, S.y , Hunt, C.y , van Dyck, , Carson, , MacAvoy, , Chertkow, , Bergman, , Hosein, , Hsiung, G.-Y.R.bk , Feldman, H.bk , Mudge, B.bk , Assaly, M.bk , Bernick, , Munic, , Kertesz, , Rogers, , Trost, , Kerwin, D.ah , Lipowski, K.ah , Wu, C.-K.ah , Johnson, N.ah , Sadowsky, , Martinez, , Villena, , Turner, , Johnson, , Reynolds, , Sperling, R.A.x , Johnson, K.A.x , Marshall, G.x , Frey, M.x , Lane, B.x , Rosen, A.x , Tinklenberg, J.x , Sabbagh, M.N.bp , Belden, C.M.bp , Jacobson, S.A.bp , Sirrel, S.A.bp , Kowall, N.bp , Killiany, , Budson, , Norbash, , Johnson, , Allard, , Lerner, , Ogrocki, , Hudson, , Fletcher, E.w , Carmichael, O.w , Olichney, J.w , DeCarli, C.w , Kittur, , Borrie, M.bu , Lee, T.-Y.bu , Bartha, R.bu , Johnson, , Asthana, , Carlsson, , Preda, , Nguyen, , Tariot, , Reeder, , Bates, , Capote, , Rainka, , Scharre, D.W.bx , Kataki, M.bx , Adeli, A.bx , Zimmerman, , Celmins, , Brown, , Pearlson, , Blank, , Anderson, , Santulli, , Kitzmiller, , Schwartz, , Sink, K.M.cb , Williamson, J.D.cb , Garg, P.cb , Watkins, F.cb , Ott, , Querfurth, , Tremont, , Salloway, , Malloy, , Correia, , Rosen, H.J.q , Miller, B.L.q , Mintzer, J.ce , Spicer, K.ce , Bachman, D.ce , Pasternak, , Rachinsky, , Drost, , Pomara, , Hernando, , Sarrael, , Schultz, , Ponto, , Shim, , Smith, , Relkin, , Chaing, , Raudin, L.aa ad , Smith, , Fargher, , Raj, , Neylan, T.q , Grafman, J.ah , Davis, M.r , Morrison, R.r , Hayes, J.q , Finley, S.q , Friedl, , Fleischman, D.ay , Arfanakis, K.ay , James, , Massoglia, D.ce , Fruehling, , Harding, , Peskind, , Petrie, E.C.bx , Li, G.bx , Yesavage, J.A.cj , Taylor, J.L.cj , Furst, A.J.cj , Mok, V.C.T.e , Kwok, T.C.Y.f , Mok, K.Y.a b g h , Shoai, M.g h , Lehallier, B.i ck , Losada, P.M.i j , O’Brien, E.k l , Porter, T.k l m , Laws, S.M.k l m , Hardy, J.b g h n , Wyss-Coray, T.b i j o , Masters, C.L.p , Fu, A.K.Y.a b c , Ip, N.Y.a b c , Alzheimer’s Disease Neuroimaging Initiativecl

a Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
b Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong
c Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development; Shenzhen–Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, China
d The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen–Hong Kong Institute of Brain Science–Shenzhen Fundamental Research Institutions, Shenzhen, China
e Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
f Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
g Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
h UK Dementia Research Institute, University College London, London, United Kingdom
i Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
j Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
k Centre for Precision Health, Edith Cowan University, Joondalup, Australia
l Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
m School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia
n Institute for Advanced Study, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
o The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
p The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
q UC San Francisco, San Francisco, CA, United States
r UC San Diego, San Diego, CA, United States
s Mayo Clinic, Rochester, NY, United States
t UC Berkeley, Berkeley, CA, United States
u University of Pennsylvania, Philadelphia, PA, United States
v University of Southern California, Los Angeles, CA, United States
w UC Davis, Davis, CA, United States
x Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, United States
y Indiana University, Bloomington, IN, United States
z Washington University in St. Louis, St. Louis, MO, United States
aa Prevent Alzheimer’s Disease 2020, Rockville, MD, United States
ab Siemens, Munich, Germany
ac University of Pittsburgh, Pittsburgh, PA, United States
ad Weill Cornell Medical College, Cornell University, New York City, NY, United States
ae Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, United States
af Alzheimer’s Drug Discovery Foundation, New York City, NY, United States
ag Acumen Pharmaceuticals, Livermore, CA, United States
ah Northwestern University, Evanston and Chicago, Evanston, IL, United States
ai National Institute of Mental Health, Rockville, MD, United States
aj Brown University, Providence, RI, United States
ak Eli Lilly, IndianapolisIN, United States
al University of Washington, Seattle, WA, United States
am UCLA, Los Angeles, CA, United States
an University of Michigan, Ann Arbor, MI, United States
ao University of Utah, Salt Lake City, UT, United States
ap Banner Alzheimer’s Institute, Phoenix, AZ, United States
aq UC Irvine, Irvine, CA, United States
ar National Institute on Aging, Bethesda, MD, United States
as Johns Hopkins University, Baltimore, MD, United States
at Richard Frank ConsultingWA, United States
au Oregon Health and Science University, Portland, OR, United States
av Baylor College of Medicine, Houston, TX, United States
aw University of Alabama, Birmingham, AL, United States
ax Mount Sinai School of Medicine, New York City, NY, United States
ay Rush University Medical Center, Chicago, IL, United States
az Wien Center, Miami, FL, United States
ba New York University, New York City, NY, United States
bb Duke University Medical Center, Durham, NC, United States
bc University of Kentucky, Lexington, KY, United States
bd University of Rochester Medical Center, Rochester, NY, United States
be University of Texas Southwestern Medical School, Dallas, TX, United States
bf Emory University, Atlanta, GA, United States
bg Medical Center, University of Kansas, Kansas City, KS, United States
bh Mayo Clinic, Jacksonville, FL, United States
bi Yale University School of Medicine, New Haven, CT, United States
bj McGill University/Montreal-Jewish General Hospital, Montreal, QC, Canada
bk University of British Columbia Clinic for Alzheimer’s Disease and Related Disorders, Vancouver, BC, Canada
bl Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
bm St Joseph’s Health Care, London, ON, Canada
bn Premiere Research Institute, Palm Beach Neurology, Miami, FL, United States
bo Georgetown University Medical Center, Washington, DC, United States
bp Banner Sun Health Research Institute, Sun City, AZ, United States
bq Boston University, Boston, MA, United States
br Howard University, Washington, DC, United States
bs Case Western Reserve University, Cleveland, OH, United States
bt Neurological Care of CNY, Liverpool, NY, United States
bu Parkwood Hospital, London, ON, Canada
bv University of Wisconsin, Madison, WI, United States
bw Dent Neurologic Institute, Amherst, NY, United States
bx Ohio State University, Columbus, OH, United States
by Albany Medical College, Albany, NY, United States
bz Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford, CT, United States
ca Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
cb Wake Forest University Health Sciences, Winston-Salem, NC, United States
cc Rhode Island Hospital, Providence, RI, United States
cd Butler Hospital, Providence, RI, United States
ce Medical University South Carolina, Charleston, SC, United States
cf Nathan Kline Institute, Orangeburg, NY, United States
cg University of Iowa College of Medicine, Iowa City, IA, United States
ch USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL, United States
ci Department of Defense, Arlington, VA, United States
cj Stanford University, Stanford, CA, United States
ck Alkahest Inc, San Carlos, CA, United States

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD. © 2022, The Author(s).

Funding details
National Institute on AgingNIA
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Alzheimer’s Disease Neuroimaging InitiativeADNI
Science and Industry Endowment FundSIEF
Medical Research CouncilMRC
Alzheimer’s Society
National Health and Medical Research CouncilNHMRCAPP1161706
Commonwealth Scientific and Industrial Research OrganisationCSIRO
Institut National de la Santé et de la Recherche MédicaleInserm
Edith Cowan UniversityECU
National Natural Science Foundation of ChinaNSFC31671047
University Grants CommitteeUGCAoE/M-604/16
Alzheimer’s Research UKARUK
Research Grants Council, University Grants Committee研究資助局T13-605/18-W
Dementia Collaborative Research Centres, AustraliaDCRC
Innovation and Technology CommissionITCINNOHK18SC01, ITCPD/17-9, MRP/042/18X
State Government of Victoria
National Key Research and Development Program of ChinaNKRDPC2017YFE0190000, 2018YFE0203600
Australian Alzheimer’s Research Foundation
Yulgilbar Foundation
Shenzhen Knowledge Innovation ProgramJCYJ20170413173717055, JCYJ20180507183642005

Document Type: Article
Publication Stage: Final
Source: Scopus