Scopus list of publications for March 19, 2023
Impaired neurogenesis with reactive astrocytosis in the hippocampus in a porcine model of acquired hydrocephalus
(2023) Experimental Neurology, 363, art. no. 114354, .
Garcia-Bonilla, M.a , Nair, A.a , Moore, J.a , Castaneyra-Ruiz, L.b , Zwick, S.H.a , Dilger, R.N.c , Fleming, S.A.c d , Golden, R.K.c , Talcott, M.R.a e , Isaacs, A.M.f , Limbrick, D.D., Jra , McAllister, J.P., IIa
a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
b CHOC Children’s Research Institute, 1201 W. La Veta Avenue, Orange, CA 92868, United States
c Neuroscience Program, Department of Animal Sciences, University of Illinois, Urbana-Champaign, IL 61801, United States
d Traverse Science, Champaign, IL 61801, United States
e AbbVie, Inc., North Chicago, IL 60064, United States
f Department of Neurological Surgery, Vanderbilt, University Medical Center, Nashville, TN 37232, United States
Background: Hydrocephalus is a neurological disease with an incidence of 0.3–0.7 per 1000 live births in the United States. Ventriculomegaly, periventricular white matter alterations, inflammation, and gliosis are among the neuropathologies associated with this disease. We hypothesized that hippocampus structure and subgranular zone neurogenesis are altered in untreated hydrocephalus and correlate with recognition memory deficits. Methods: Hydrocephalus was induced by intracisternal kaolin injections in domestic juvenile pigs (43.6 ± 9.8 days). Age-matched sham controls received similar saline injections. MRI was performed to measure ventricular volume, and/or hippocampal and perirhinal sizes at 14 ± 4 days and 36 ± 8 days post-induction. Recognition memory was assessed one week before and after kaolin induction. Histology and immunohistochemistry in the hippocampus were performed at sacrifice. Results: The hippocampal width and the perirhinal cortex thickness were decreased (p < 0.05) in hydrocephalic pigs 14 ± 4 days post-induction. At sacrifice (36 ± 8 days post-induction), significant expansion of the cerebral ventricles was detected (p = 0.005) in hydrocephalic pigs compared with sham controls. The area of the dorsal hippocampus exhibited a reduction (p = 0.035) of 23.4% in the hydrocephalic pigs at sacrifice. Likewise, in hydrocephalic pigs, the percentages of neuronal precursor cells (doublecortin+ cells) and neurons decreased (p < 0.01) by 32.35%, and 19.74%, respectively, in the subgranular zone of the dorsal hippocampus. The percentage of reactive astrocytes (vimentin+) was increased (p = 0.041) by 48.7%. In contrast, microglial cells were found to decrease (p = 0.014) by 55.74% in the dorsal hippocampus in hydrocephalic pigs. There was no difference in the recognition index, a summative measure of learning and memory, one week before and after the induction of hydrocephalus. Conclusion: In untreated juvenile pigs, acquired hydrocephalus caused morphological alterations, reduced neurogenesis, and increased reactive astrocytosis in the hippocampus and perirhinal cortex. © 2023
Acquired hydrocephalus; Hippocampus; Neurogenesis; Neuroinflammation; Perirhinal cortex; Pig model; Recognition memory
National Institutes of HealthNIH5R21NS111249–02
Document Type: Article
Publication Stage: Final
Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy
(2023) Nature, . Cited 1 time.
Chen, X.a , Firulyova, M.b , Manis, M.a , Herz, J.c d , Smirnov, I.c d , Aladyeva, E.c , Wang, C.a , Bao, X.a , Finn, M.B.a , Hu, H.a , Shchukina, I.c , Kim, M.W.c d , Yuede, C.M.a , Kipnis, J.a c d , Artyomov, M.N.c , Ulrich, J.D.a , Holtzman, D.M.a d
a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
b Almazov National Medical Research Centre, St Petersburg, Russian Federation
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
d Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St Louis, MO, United States
Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease1,2. The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition3–5, and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology6. Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies. © 2023, The Author(s), under exclusive licence to Springer Nature Limited.
National Institutes of HealthNIHNS090934
Foundation for Barnes-Jewish HospitalFBJH3770, 4642
Cure Alzheimer’s FundCAF
Rainwater Charitable FoundationRCF
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
Ministry of Education and Science of the Russian FederationMinobrnauka075-15-2022-301
Document Type: Article
Publication Stage: Article in Press
Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts
(2023) Nature Medicine, .
Kundishora, A.J.a , Allington, G.b c , McGee, S.d , Mekbib, K.Y.a c , Gainullin, V.d , Timberlake, A.T.e , Nelson-Williams, C.f , Kiziltug, E.a , Smith, H.a c , Ocken, J.a , Shohfi, J.a , Allocco, A.a , Duy, P.Q.a , Elsamadicy, A.A.a , Dong, W.g , Zhao, S.h , Wang, Y.-C.h , Qureshi, H.M.a , DiLuna, M.L.a , Mane, S.h i , Tikhonova, I.R.j , Fu, P.-Y.h , Castaldi, C.i , López-Giráldez, F.i , Knight, J.R.i , Furey, C.G.a , Carter, B.S.c , Haider, S.k , Moreno-De-Luca, A.l , Alper, S.L.m n , Gunel, M.a , Millan, F.d , Lifton, R.P.g , Torene, R.I.d , Jin, S.C.h o , Kahle, K.T.a c p q
a Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
b Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
c Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, United States
d GeneDx, Gaithersburg, MD, United States
e Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, NY, United States
f Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
g Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
h Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
i Yale Center for Genomic Analysis, Yale University, West Haven, CT, United States
j School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom
k School of Pharmacy, University College London, London, United Kingdom
l Department of Radiology, Autism and Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA, United States
m Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
n Department of Medicine, Harvard Medical School, Boston, MA, United States
o Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
p Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
q Broad Institute of MIT and Harvard, Cambridge, MA, United States
Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient–parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10−33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease. © 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.
National Institutes of HealthNIH5U54HG006504, K12 228168, R01 NS109358, R01 NS111029-01A1
Howard Hughes Medical InstituteHHMI
National Institute of General Medical SciencesNIGMST32GM007205
National Center for Advancing Translational SciencesNCATSR00HL143036, TL1 TR001864
Children’s Discovery InstituteCDICDI-FR-2021-926
Rudi Schulte Research InstituteRSRI
Document Type: Article
Publication Stage: Article in Press
Targeting nonsense-mediated RNA decay does not increase progranulin levels in the Grn R493X mouse model of frontotemporal dementia
(2023) PLoS ONE 18(3): e0282822.
Smith DM, Niehoff ML, Ling K, Jafar-Nejad P, Rigo F, Farr SA, and Nguyen AD.
A common cause of frontotemporal dementia (FTD) are nonsense mutations in the progranulin (GRN) gene. Because nonsense mutations activate the nonsense-mediated RNA decay (NMD) pathway, we sought to inhibit this RNA turnover pathway as a means to increase progranulin levels. Using a knock-in mouse model harboring a common patient mutation, we tested whether either pharmacological or genetic inhibition of NMD upregulates progranulin in these GrnR493X mice. We first examined antisense oligonucleotides (ASOs) targeting an exonic region in GrnR493X mRNA predicted to block its degradation by NMD. As we previously reported, these ASOs effectively increased GrnR493X mRNA levels in fibroblasts in vitro. However, following CNS delivery, we found that none of the 8 ASOs we tested increased Grn mRNA levels in the brains of GrnR493X mice. This result was obtained despite broad ASO distribution in the brain. An ASO targeting a different mRNA was effective when administered in parallel to wild-type mice. As an independent approach to inhibit NMD, we examined the effect of loss of an NMD factor not required for embryonic viability: UPF3b. We found that while Upf3b deletion effectively perturbed NMD, it did not increase Grn mRNA levels in Grn+/R493X mouse brains. Together, our results suggest that the NMD-inhibition approaches that we used are likely not viable for increasing progranulin levels in individuals with FTD caused by nonsense GRN mutations. Thus, alternative approaches should be pursued. Copyright: © 2023 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.