143 results on '"Audrain, M."'
Search Results
2. Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer’s Disease Predementia
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Souchet, B., Audrain, M., Alves, S., Fol, R., Tada, S., Orefice, N. S., Potier, B., Dutar, P., Billard, J.-M., Cartier, Nathalie, and Braudeau, Jérôme
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- 2022
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3. Erratum to: Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats
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Souchet, B., Audrain, M., Gu, Y., Lindberg, M. F., Orefice, N. S., Rey, E., Cartier, N., Janel, N., Meijer, L., and Braudeau, Jérôme
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- 2023
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4. Review: Why screen for severe combined immunodeficiency disease?
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Thomas, C., Hubert, G., Catteau, A., Danielo, M., Riche, V.P., Mahlaoui, N., Moshous, D., and Audrain, M.
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- 2020
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5. Dépistage néonatal des déficits immunitaires combinés sévères: présentation de l'étude DEPISTREC
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Thomas, C., Mirallié, S., Audrain, M, and Dert, C.
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- 2015
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6. HNA-3 genotyping by PCR-SSP and small amplicon PCR-HRM without probes.: T6-PO52
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Quelvennec, E, Fromont, P, Audrain, M, and Josien, R CHU
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- 2010
7. Anti-granulocyte antibody screening: evaluation of a bead-based assay in comparison with classical methods: T6-PO47
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Fromont, P, Prie, N, Simon, P, Cesbron-Gautier, A, Quelvennec, E, Bignon, J D, Muller, J Y, and Audrain, M
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- 2010
8. Auto-immune neutropenia in children: analysis of 116 cases: T6-PO45
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Audrain, M, Martin, J, Fromont, P, Prie, N, Thomas, C, and Muller, J YCHU
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- 2010
9. Theme 07 - PRE-CLINICAL THERAPEUTIC STRATEGIES.
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Burg, T., Rossaert, E., Moisse, M., Van Damme, P., Van Den Bosch, L., Niblock, M., Sreedharan, J., Seredenina, T., Afroz, T., Chevalier, E., Ziehm, T., Audrain, M., Egesipe, A., Mottier, L., Neumann, M., Havas, D., Ollier, R., Piorkowska, K., Chauhan, M., and Dumayne, C.
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LEWY body dementia ,AMYOTROPHIC lateral sclerosis ,LABORATORY mice ,MOTOR neurons ,PYRAMIDAL tract - Abstract
T-type Ca 2+ enhancer SAK3 activates CaMKII and proteasome activities in Lewy body dementia mice model. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. [Extracted from the article]
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- 2021
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10. Quantification of human cytoplasmic islet-cell antibodies which cross-react with mouse pancreas: a follow-up study in Type 1 (insulin-dependent) diabetic patients and in first-degree relatives
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Saï, P., Elmansour, A., Audrain, M., Charbonnel, B., and Bardet, S.
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- 1993
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11. Difference in antigenic determinant profiles between human and rat myeloperoxidase
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PATRY, Y. C., NACHMAN, P. H., AUDRAIN, M. A.P., FALK, R. J., MEFLAH, K., and ESNAULT, V. L.M.
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- 2003
12. Poor predictive value of antinucleosome and antineutrophil cytoplasmic antibodies in a 270 inception cohort of patients with early naked arthritis of less than one yearʼs duration
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Berthelot, J-M, Saraux, A, Audrain, M, Le Goff, P, Hamidou, M, Muller, J-Y, and Youinou, P
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- 2002
13. Value of autoantibodies to β2-glycoprotein 1 in the diagnosis of antiphospholipid syndrome
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Audrain, M. A. P., El Kouri, D., Hamidou, M. A., Mioche, L., Ibara, A., Langlois, M.-L., and Muller, J.-Y.
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- 2002
14. Systemic antineutrophil cytoplasmic antibody vasculitis associated with lymphoid neoplasia
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Hamidou, M A, El Kouri, D, Audrain, M, and Grolleau, J-Y
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- 2001
15. Newborn Screening for Severe Combined Immunodeficiency: Analytic and Clinical Performance of the T Cell Receptor Excision Circle Assay in France (DEPISTREC Study)
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Audrain, M. A. P., Leger, A. J. C., Hemont, C. A. F., Mirallie, S. M., Cheillan, David, Rimbert, M. G. M., Le Thuaut, A. M. P., Sebille-Rivain, V. A., Prat, A., Pinel, E. M. Q., Divry, E., Dert, C. G. L., Fournier, M. A. G., Thomas, C. J. C., Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)
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Newborn screening ,clinical performance ,experience ,[SDV]Life Sciences [q-bio] ,Immunology ,T cell ,severe combined immunodeficiency (SCID) ,lymphopenia ,analytic performance ,1st 2 years ,receptor excision circle (TREC) quantification - Abstract
Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high-throughput SCID screening. Clinical Trials: NCT02244450
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- 2018
16. Anti-native and recombinant myeloperoxidase monoclonals and human autoantibodies
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Audrain, M. A. P., Baranger, T. A. R., Moguilevski, N., Martin, S. J., Devys, A., Lockwood, C. M., Muller, J. Y., and Esnault, V. L. M.
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- 1997
17. Exploration des déficits immunitaires primitifs.
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Thomas, C. and Audrain, M.
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Les déficits immunitaires primitifs sont des maladies génétiques qui touchent l'immunité adaptative ou innée. À ce jour, environ 300 gènes impliqués sont connus. Les déficits immunitaires primitifs sont classés en fonction des cellules atteintes en déficits combinés, humoraux, anomalies des cellules phagocytaires, déficits de l'immunité innée, défauts de régulation de la réponse immune. Les manifestations révélatrices des déficits immunitaires primitifs sont surtout les infections mais d'autres signes d'appel sont possibles : allergies sévères, cassure de la courbe staturopondérale, manifestations auto-immunes, cancers ou manifestations syndromiques associées. Dans la plupart des cas, les éléments de l'interrogatoire, l'examen clinique et les types de complications observées, associées à des examens biologiques simples de première intention permettent d'orienter le diagnostic sur un type de déficit immunitaire et de cibler les examens à réaliser en deuxième intention. Les examens biologiques de première et de seconde ligne sont souvent complétés par des analyses génétiques qui permettent de confirmer l'anomalie moléculaire suspectée et de proposer un conseil au sein de la famille. [ABSTRACT FROM AUTHOR]
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- 2019
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18. Stability of newborn screening markers in dried-blood spot: The innovative imagene solution
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Amintas, S., Coudy, D., Cheillan, D., Garnotel, R., Perini, J., Audrain, M., Tuffet, S., and Mesli, S.
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- 2019
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19. Systematic screening for nonspecific autoantibodies in idiopathic sensorineural hearing loss: no association with steroid response.
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Hervier B, Bordure P, Audrain M, Calais C, Masseau A, and Hamidou M
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- 2010
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20. Prevalence of rheumatic manifestations and antineutrophil cytoplasmic antibodies in haematological malignancies. A prospective study.
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Hamidou, M. A., Derenne, S., Audrain, M. A. P., Berthelot, J. M., Boumalassa, A., and Grolleau, J. Y.
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- 2000
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21. Alpha1-antitrypsin phenotypes and anti-neutrophil cytoplasmic auto-antibodies in inflammatory bowel disease.
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Taddei, Catherine, Audrain, Marie A. P., Reumaux, Dominique, Sesboüe, Richard, Testa, Angelo, Galmiche, Jean-Paul, Duthilleul, Patrick, Colombel, Jean Frédéric, M. Esnault, Vincent L, Taddei, C, Audrain, M A, Reumaux, D, Sesboüe, R, Testa, A, Galmiche, J P, Duthilleul, P, Colombel, J F, and Esnault, V L
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- 1999
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22. Antineutrophil cytoplasmic antibodies (ANCA) in chronic graft-versus-host disease after allogeneic bone marrow transplantation.
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Martin, S J, Audrain, M A P, Oksman, F, Ecoiffier, M, Attal, M, Milpied, N, and Esnault, V L M
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GRAFT versus host disease , *BONE marrow transplant complications - Abstract
We studied the usefulness of monitoring antineutrophil cytoplasmic antibodies (ANCA) in chronic graft-versus-host disease (cGVHD), a major complication of allogeneic bone marrow transplantation. Antigen-specific ELISA and indirect immunofluorescence (IIF) were used to search for ANCA in 47 allogeneic bone marrow graft recipients who developed cGVHD and in 43 who did not (controls). Eight patients exhibited ANCA IIF positivity in the cGVHD group, but none in the controls. Specificity was confirmed in antigen-specific assays in only two cGVHD patients, both showing antilactoferrin (anti-LF) activity. One of these patients was followed-up, and antilactoferrin antibodies were found only at the time of active but limited cGVHD. Among three ANCA IIF-positive patients, two had antinuclear autoantibodies and three antineutrophil alloantibodies secondary to blood transfusion, which may have been responsible for false ANCA IIF positivity. It is concluded that ANCA determination is not useful in patients with cGVHD. Polyclonal activation of B lymphocytes could result in ANCA activity during cGVHD. False-positive ANCA could be due to allo-immunization following blood transfusion. Rare patients may present antilactoferrin antibodies of unknown clinical significance. [ABSTRACT FROM AUTHOR]
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- 1997
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23. Anti-Neutrophil Cytoplasm Antibodies in Patients with ACR Criteria for Polyarteritis Nodosa: Help for Systemic Vasculitis Classification?
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Baranger, T. A. R., Audrain, M. A. P., Testa, A., Besnier, D., Guillevin, L., and Esnault, V. L. M.
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- 1995
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24. SPECIFICITY OF ANTIPERINUCLEAR FACTOR FOR RHEUMATOID ARTHRITIS IN RHEUMATOID FACTOR-POSITIVE SERA.
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BERTHELOT, J. M., MAUGARS, Y., AUDRAIN, M., YOUINOU, P., and PROST, A.
- Abstract
Although antiperinuclear factor (APF) has the same specificity for rheumatoid arthritis (RA) as rheumatoid factor (RF), there is no evidence that this specificity is maintained in patients with positive RF-agglutination tests. Thus, we evaluated the specificity and usefulness of APF for RA diagnosis, regardless of RF titre. APF was tested (1:100 threshold) on 214 sera sent for RF evaluation over a 9-month period. These sera were previously determined to have latex or Rose-Waaler (RW) titres ≥ 12 or 4 IU, respectively, but not necessarily above the threshold values of 100 and 32 IU. The APF test was performed blindly, and physicians were not advised of the results. In the patient population (119 RA and 95 non-RA) APF still demonstrated good specificity (0.82) for RA. As expected, APF proved useful for RA diagnosis in 28/33 (85%) RA cases with an RF level below 1:100 for latex and 1:32 for RW, thus reducing the number of ‘seronegative’ RA from 33/119 to 5/119. However, it also improved the serological positive predictive value for RA, even in cases when RW results were ≥32 IU. Indeed, the positive predictive value for RA when both tests were positive was 0.94 (68/72), whereas concordant results (either positive or negative) for both APF and RW tests allowed correct classification (RA or non-RA) in 94% of cases. [ABSTRACT FROM PUBLISHER]
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- 1995
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25. Two cases of atypical Whipple's disease associated with cytoplasmic ANCA of undefined specificity.
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Agard C, Brisseau JM, Grossi O, Pattier S, Espitia-Thibault A, Le Goff B, Audrain M, Ponge T, and Hamidou M
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- 2012
26. Evaluation of the tuberculin skin test and the interferon-gamma release assay for TB screening in French healthcare workers.
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Tripodi D, Brunet-Courtois B, Nael V, Audrain M, Chailleux E, Germaud P, Naudin F, Muller J, Bourrut-Lacouture M, Durand-Perdriel M, Gordeeff C, Guillaumin G, Houdebine M, Raffi F, Boutoille D, Biron C, Potel G, Roedlich C, Geraut C, and Schablon A
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- 2009
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27. CERVICAL LEUCO-MELANODERMIE IN HEREDITARY SYPHILIS.
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Audrain, M.
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- 1908
28. TREATMENT OF PRURIGO OF HEBRA WITH BOULLION OF FRESH PORK LIVER.
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Audrain, M.
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- 1908
29. Evaluation of two antibodies against double-stranded DNA assays in discriminating between active and non-active systemic lupus erythematosus: Correlation between the cut-off and the specificity
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Martin, J., Durant, C., Rimbert, M., Hemont, C., Hamidou, M., and Audrain, M.
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DNA antibodies , *SYSTEMIC lupus erythematosus , *IMMUNOSPECIFICITY , *COMPARATIVE studies , *BIOLOGICAL assay , *LABORATORY equipment & supplies , *EVALUATION - Abstract
Abstract: This study aimed to evaluate, improve and compare the performances of two anti-double-stranded DNA (dsDNA) detection kits, differing by their affinity, in discriminating between active and non-active systemic lupus erythematosus (SLE). Eighty-two anti-nuclear antibody positive sera (45 patients) were tested by two anti-dsDNA commercial quantitative assays (Fidis™, Farrzyme™). All the patients fulfilled at least four of the revised American College of Rheumatology criteria. SLE disease activity was assessed using a modified SLEDAI to remove anti-dsDNA descriptors. When using the manufacturers’ cut-offs, no difference in the frequency of positive results was found with respect to disease activity, with Fidis™. On the contrary, with Farrzyme™, a significantly higher frequency of positive sera was found in active SLE patients. Nonetheless, poor performances were observed for both tests. With thresholds defined by ROC methodology, 212IU/mL for Fidis™ (Se: 83.9%, Sp: 86.3%), and 68.8IU/mL for Farrzyme (Se: 71.0%, Sp: 96.1%), a great improvement of the accuracy of the two methods was observed. Moreover, the better specificity and pLR, obtained after optimization of the Farrzyme™ test, could also be obtained with the Fidis™ assay by using a higher threshold than that obtained after optimization of the test. We concluded that when using manufacturers’ cut-offs, the two assays appeared to be of poor clinical usefulness in the determination of disease activity. A great improvement was observed using higher thresholds. Moreover, a good concordance could be observed between the two assays (κ=0.764). [Copyright &y& Elsevier]
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- 2012
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30. Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.
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Pan AL, Audrain M, Sakakibara E, Joshi R, Zhu X, Wang Q, Wang M, Beckmann ND, Schadt EE, Gandy S, Zhang B, Ehrlich ME, and Salton SR
- Abstract
Introduction: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer's disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model., Methods: To investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP., Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß
1-40 and Aß1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of "microglial clusters," which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs ( p < 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD., Discussion: In summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pan, Audrain, Sakakibara, Joshi, Zhu, Wang, Wang, Beckmann, Schadt, Gandy, Zhang, Ehrlich and Salton.)- Published
- 2024
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31. Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.
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Audrain M, Egesipe AL, Tentillier N, Font L, Ratnam M, Mottier L, Clavel M, Le Roux-Bourdieu M, Fenyi A, Ollier R, Chevalier E, Guilhot F, Fuchs A, Piorkowska K, Carlyle B, Arnold SE, Berry JD, Luthi-Carter R, Adolfsson O, Pfeifer A, Kosco-Vilbois M, Seredenina T, and Afroz T
- Abstract
In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients., Competing Interests: T.A. and T.S. are co-inventors on a patent application, publication number WO2020/234473. R.O., T.A. and T.S. are co-inventors on a patent application, publication number WO2022/034228. M.A., L.F., R.O., M.R., M.L.R.-B., E.C., A.F. , A.F.U, K.P., R.L.-C., O.A., A.P., M.K.-V., T.S. and T.A. are employees of AC Immune and entitled to options and/or shares. N.T., A.-L.E., M.C. and L.M. were employees of AC Immune at the time of this study. The other authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2023
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32. World human neutrophil antigens investigation survey.
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Bayat B, Lowack J, Audrain M, Croisille L, Curtis B, Dangerfield R, Esmaeili B, Grabowski C, Keller M, Kim H, Kroll H, Kvanka MM, Kwok J, Moritz E, Nathalang O, Nelson D, Nielsen KR, Pahn G, Poles A, Porcelijn L, Sachs UJ, Schönbacher M, Körmöczi GF, Kupatawintu P, Takahashi D, Uhrynowska M, Flesch B, and Fung YL
- Subjects
- Adult, Humans, Granulocytes, Antibodies, Surveys and Questionnaires, Neutrophils, Neutropenia
- Abstract
Background and Objectives: Human neutrophil antigens (HNAs) are categorized into five systems: HNA-1 to HNA-5. Given the importance of neutrophils in immunity, we sought to create awareness of the role of HNA diagnostic services in managing immune neutropenia and transfusion-related acute lung injury. To provide health communities all around the world with access to these services, we conducted a survey to create a directory of these HNA diagnostic services., Materials and Methods: An Excel table-based survey was created to capture information on the laboratory's location and was emailed to 55 individuals with known or possible HNA investigation activity. The collected data were then summarized and analysed., Results: Of contacted laboratories, the surveys were returned from 23 (38.2%) laboratories; 17 have already established HNA diagnostic (of them 12 were regular participants of the International Granulocyte Immunobiology Workshop [ISBT-IGIW]), 4 laboratories were in the process of establishing their HNA investigation and the remaining 2 responder laboratories, did not conduct HNA investigations. In established laboratories, investigation for autoimmune neutropenia (infancies and adults) was the most frequently requested, and antibodies against HNA-1a and HNA-1b were the most commonly detected., Conclusion: The directory of survey respondents provides a resource for health professionals wanting to access HNA diagnostic services. The present study offers a comprehensive picture of HNA diagnostics (typing and serology), identifying weak points and areas for improvement for the first time. Identifying more laboratories involved in HNA diagnostics with limited access to international societies in the field will globally improve HNA diagnostics., (© 2023 Institute of Clinical Immunology and Transfusion Medicine and The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)
- Published
- 2023
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33. Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.
- Author
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Pan AL, Audrain M, Sakakibara E, Joshi R, Zhu X, Wang Q, Wang M, Beckmann ND, Schadt EE, Gandy S, Zhang B, Ehrlich ME, and Salton SR
- Abstract
Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model., Methods: AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis., Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß
1-40 and Aß1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation and microgliosis, which are increased in 5xFAD mice, were significantly reduced by dHc DUSP6 overexpression in both males and females. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulated expression of genes involved in inflammatory and extracellular signal-regulated kinase (ERK) pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. A limited number of differentially expressed genes (DEGs) (FDR<0.05) were identified in male mice; gene ontology analysis of DEGs (p<0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Notably, the msh homeobox 3 gene, Msx3 , previously shown to regulate microglial M1/M2 polarization and reduce neuroinflammation, was one of the most robustly upregulated genes in female and male wild type and 5xFAD mice overexpressing DUSP6., Conclusions: In summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.- Published
- 2023
- Full Text
- View/download PDF
34. Effect of Aging and a Dual Orexin Receptor Antagonist on Sleep Architecture and Non-REM Oscillations Including an REM Behavior Disorder Phenotype in the PS19 Mouse Model of Tauopathy.
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Kam K, Vetter K, Tejiram RA, Pettibone WD, Shim K, Audrain M, Yu L, Daehn IS, Ehrlich ME, and Varga AW
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- Male, Female, Mice, Animals, Orexin Receptor Antagonists pharmacology, Sleep physiology, Phenotype, REM Sleep Behavior Disorder, Tauopathies drug therapy
- Abstract
The impact of tau pathology on sleep microarchitecture features, including slow oscillations, spindles, and their coupling, has been understudied, despite the proposed importance of these electrophysiological features toward learning and memory. Dual orexin receptor antagonists (DORAs) are known to promote sleep, but whether and how they affect sleep microarchitecture in the setting of tauopathy is unknown. In the PS19 mouse model of tauopathy MAPT (microtubule-associated protein tau) P301S (both male and female), young PS19 mice 2-3 months old show a sleep electrophysiology signature with markedly reduced spindle duration and power and elevated slow oscillation (SO) density compared with littermate controls, although there is no significant tau hyperphosphorylation, tangle formation, or neurodegeneration at this age. With aging, there is evidence for sleep disruption in PS19 mice, characterized by reduced REM duration, increased non-REM and REM fragmentation, and more frequent brief arousals at the macrolevel and reduced spindle density, SO density, and spindle-SO coupling at the microlevel. In ∼33% of aged PS19 mice, we unexpectedly observed abnormal goal-directed behaviors in REM, including mastication, paw grasp, and forelimb/hindlimb extension, seemingly consistent with REM behavior disorder (RBD). Oral administration of DORA-12 in aged PS19 mice increased non-REM and REM duration, albeit with shorter bout lengths, and increased spindle density, spindle duration, and SO density without change to spindle-SO coupling, power in either the SO or spindle bands, or the arousal index. We observed a significant effect of DORA-12 on objective measures of RBD, thereby encouraging future exploration of DORA effects on sleep-mediated cognition and RBD treatment. SIGNIFICANCE STATEMENT The specific effect of tauopathy on sleep macroarchitecture and microarchitecture throughout aging remains unknown. Our key findings include the following: (1) the identification of a sleep EEG signature constituting an early biomarker of impending tauopathy; (2) sleep physiology deteriorates with aging that are also markers of off-line cognitive processing; (3) the novel observation that dream enactment behaviors reminiscent of RBD occur, likely the first such observation in a tauopathy model; and (4) a dual orexin receptor antagonist is capable of restoring several of the sleep macroarchitecture and microarchitecture abnormalities., (Copyright © 2023 the authors.)
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- 2023
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35. Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD.
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Afroz T, Chevalier E, Audrain M, Dumayne C, Ziehm T, Moser R, Egesipe AL, Mottier L, Ratnam M, Neumann M, Havas D, Ollier R, Piorkowska K, Chauhan M, Silva AB, Thapa S, Stöhr J, Bavdek A, Eligert V, Adolfsson O, Nelson PT, Porta S, Lee VM, Pfeifer A, Kosco-Vilbois M, and Seredenina T
- Subjects
- Mice, Animals, Neuroprotection, DNA-Binding Proteins metabolism, Immunotherapy, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Alzheimer Disease genetics, Pick Disease of the Brain
- Abstract
Effective therapies are urgently needed to safely target TDP-43 pathology as it is closely associated with the onset and development of devastating diseases such as frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 pathology is present as a co-pathology in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Our approach is to develop a TDP-43-specific immunotherapy that exploits Fc gamma-mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP-43 function. Thus, using both in vitro mechanistic studies in conjunction with the rNLS8 and CamKIIa inoculation mouse models of TDP-43 proteinopathy, we identified the key targeting domain in TDP-43 to accomplish these therapeutic objectives. Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs (RRM) reduces TDP-43 pathology and avoids neuronal loss in vivo. We demonstrate that this rescue is dependent on Fc receptor-mediated immune complex uptake by microglia. Furthermore, monoclonal antibody (mAb) treatment enhances phagocytic capacity of ALS patient-derived microglia, providing a mechanism to restore the compromised phagocytic function in ALS and FTD patients. Importantly, these beneficial effects are achieved while preserving physiological TDP-43 activity. Our findings demonstrate that a mAb targeting the C-terminal domain of TDP-43 limits pathology and neurotoxicity, enabling clearance of misfolded TDP-43 through microglia engagement, and supporting the clinical strategy to target TDP-43 by immunotherapy. SIGNIFICANCE STATEMENT: TDP-43 pathology is associated with various devastating neurodegenerative disorders with high unmet medical needs such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Thus, safely and effectively targeting pathological TDP-43 represents a key paradigm for biotechnical research as currently there is little in clinical development. After years of research, we have determined that targeting the C-terminal domain of TDP-43 rescues multiple patho-mechanisms involved in disease progression in two animal models of FTD/ALS. In parallel, importantly, our studies establish that this approach does not alter the physiological functions of this ubiquitously expressed and indispensable protein. Together, our findings substantially contribute to the understanding of TDP-43 pathobiology and support the prioritization for clinical testing of immunotherapy approaches targeting TDP-43., Competing Interests: Declaration of Competing Interest T.A., T.S. and T.Z. are coinventors on a patent application, publication number WO2020/234473 entitled “ANTI-TDP-43 BINDING MOLECULES AND USES THEREOF.” T.A., T.S., E.C., A.E., L.M. M.A., R.M., R.O., K.P., M.C., C.D., A.B.S., V.E., O.A., A.P. and M.K are employees of AC Immune and entitled to options and/or shares. A.B., J.S. A.E., and T.Z. were employees of AC Immune at the time of this study. M.N., V.L. and S.P. received research funding from AC Immune. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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36. Improved antibody pharmacokinetics by disruption of contiguous positive surface potential and charge reduction using alternate human framework.
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Ollier R, Fuchs A, Gauye F, Piorkowska K, Menant S, Ratnam M, Montanari P, Guilhot F, Phillipe D, Audrain M, Egesipe AL, Névoltris D, Seredenina T, Pfeifer A, Kosco-Vilbois M, and Afroz T
- Subjects
- Mice, Humans, Animals, Mice, Transgenic, Metabolic Clearance Rate, Isoelectric Point, Histocompatibility Antigens Class I, Receptors, Fc, Antibodies, Monoclonal
- Abstract
Optimal pharmacokinetic (PK) properties of therapeutic monoclonal antibodies (mAbs) are essential to achieve the desired pharmacological benefits in patients. To accomplish this, we followed an approach comprising structure-based mAb charge engineering in conjunction with the use of relevant preclinical models to screen and select humanized candidates with PK suitable for clinical development. Murine mAb targeting TDP-43, ACI-5891, was humanized on a framework (VH1-3/VK2-30) selected based on the highest sequence homology. Since the initial humanized mAb (ACI-5891.1) presented a fast clearance in non-human primates (NHPs), reiteration of humanization on a less basic human framework (VH1-69-2/VK2-28) while retaining high sequence homology was performed. The resulting humanized variant, ACI-5891.9, presented a six-fold reduction in clearance in NHPs resulting in a significant increase in half-life. The observed reduced clearance of ACI-5891.9 was attributed not only to the overall reduction in isoelectric point (pI) by 2 units, but importantly to a more even surface potential. These data confirm the importance and contribution of surface charges to mAb disposition in vivo . Consistent low clearance of ACI-5891.9 in Tg32 mice, a human FcRn transgenic mouse model, further confirmed its utility for early assessment and prediction of human PK. These data demonstrate that mAb surface charge is an important parameter for consideration during the selection and screening of humanized candidates in addition to maintaining the other key physiochemical and target binding characteristics.
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- 2023
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37. Antiphospholipid syndrome in patients over 65 years: A comparative study of clinical and biological features and thrombotic relapses.
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Masson C, An Nguyen TT, Dufrost V, Audrain M, Hémont C, Agard C, Artifoni M, Connault J, Fouassier M, Hamidou M, Guedon AF, Wahl D, Zuily S, and Espitia O
- Subjects
- Humans, Male, Aged, Female, Antibodies, Anticardiolipin, Lupus Coagulation Inhibitor, Recurrence, Immunoglobulin M, Antiphospholipid Syndrome diagnosis, Lupus Erythematosus, Systemic, Thrombosis, Venous Thrombosis epidemiology
- Abstract
Objective: The aim of the study was to describe clinical and biological characteristics and thrombotic relapses of patients diagnosed with antiphospholipid syndrome (APS) after the age of 65 years, in comparison with patients diagnosed with APS before 65., Methods: This retrospective multicenter study was performed to 2005 from 2017 and included patients diagnosed with APS after the age of 65 years, in accordance with Sydney criteria. We compared these patients with APS patients diagnosed before the age of 65 years, and with control thrombotic patients older than 65 years., Results: Fifty-eight APS patients over the age of 65 years were compared to 127 APS patients aged less than 65 and to 58 controls. In elderly APS versus younger APS, there was a male predominance (58.6% vs 36.2% p = .001); myocardial infarction and lower limb deep vein thrombosis (LLDVT) were more frequent in elderly, respectively, 12.1% versus 1.6% ( p = .005), and 44.8% versus 29.9% ( p = .048). Anticardiolipin antibody (aCL) IgM was more frequently found in old patients compared to younger patients (33.9% vs 18.1%, p = .02), contrary to lupus anticoagulant (LAC) (52.8% vs 66.9%, p = .02). Older patients were more often diagnosed with single positive APS (82.8% vs 59.8% p = .002). The thrombotic relapse free survival was lower in elderly APS patients ( p = .044) compared to younger APS. Elderly APS patients had more recurrent arterial and venous thrombosis ( p = .03) and had poorer overall survival ( p = .004) than elderly controls., Conclusion: In this study, APS was different in patients aged more than 65 years, with a male predominance and more myocardial infarctions and LLDVT at diagnosis. Single antiphopholipid positivity and aCL IgM were more frequent in older patients. Older patient with APS had more thrombotic recurrence during follow-up. Compared to elderly controls, elderly APS patients had more thrombosis recurrences and poorer survival.
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- 2022
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38. Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.
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Pan AL, Audrain M, Sakakibara E, Joshi R, Zhu X, Wang Q, Wang M, Beckmann ND, Schadt EE, Gandy S, Zhang B, Ehrlich ME, and Salton SR
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- Animals, Female, Male, Mice, Extracellular Signal-Regulated MAP Kinases metabolism, Hippocampus metabolism, Learning, Alzheimer Disease genetics, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Protein Tyrosine Phosphatases genetics
- Abstract
Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on VGF (non-acronymic) as a key hub or driver. Within this computational VGF network, we identified the dual-specificity protein phosphatase 4 ( DUSP4 ) [also known as mitogen-activated protein kinase (MAPK) phosphatase 2] as an important node. Importantly, DUSP4 gene expression, like that of VGF , is downregulated in postmortem Alzheimer's disease (AD) brains. We investigated the roles that this VGF / DUSP4 network plays in the development of learning behavior impairment and neuropathology in the 5xFAD amyloidopathy mouse model. We found reductions in DUSP4 expression in the hippocampi of male AD subjects, correlating with increased CDR scores, and in 4-month-old female and 12-18-month-old male 5xFAD hippocampi. Adeno-associated virus (AAV5)-mediated overexpression of DUSP4 in 5xFAD mouse dorsal hippocampi (dHc) rescued impaired Barnes maze performance in females but not in males, while amyloid loads were reduced in both females and males. Bulk RNA sequencing of the dHc from 5-month-old mice overexpressing DUSP4, and Ingenuity Pathway and Enrichr analyses of differentially expressed genes (DEGs), revealed that DUSP4 reduced gene expression in female 5xFAD mice in neuroinflammatory, interferon-gamma (IFNγ), programmed cell death protein-ligand 1/programmed cell death protein 1 (PD-L1/PD-1), and extracellular signal-regulated kinase (ERK)/MAPK pathways, via which DUSP4 may modulate AD phenotype with gender-specificity.
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- 2022
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39. Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2.
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Haure-Mirande JV, Audrain M, Ehrlich ME, and Gandy S
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- Animals, Brain metabolism, Disease Models, Animal, Membrane Glycoproteins genetics, Membrane Glycoproteins metabolism, Mice, Microglia metabolism, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Alzheimer Disease metabolism, Amyloidosis metabolism, Membrane Proteins metabolism, Receptors, Immunologic genetics, Receptors, Immunologic metabolism, Tauopathies metabolism
- Abstract
TYROBP (also known as DAP12 or KARAP) is a transmembrane adaptor protein initially described as a receptor-activating subunit component of natural killer (NK) cells. TYROBP is expressed in numerous cell types, including peripheral blood monocytes, macrophages, dendritic cells, and osteoclasts, but a key point of recent interest is related to the critical role played by TYROBP in the function of many receptors expressed on the plasma membrane of microglia. TYROBP is the downstream adaptor and putative signaling partner for several receptors implicated in Alzheimer's disease (AD), including SIRP1β, CD33, CR3, and TREM2. TYROBP has received much of its current notoriety because of its importance in brain homeostasis by signal transduction across those receptors. In this review, we provide an overview of evidence indicating that the biology of TYROBP extends beyond its interaction with these four ligand-binding ectodomain-intramembranous domain molecules. In addition to reviewing the structure and localization of TYROBP, we discuss our recent progress using mouse models of either cerebral amyloidosis or tauopathy that were engineered to be TYROBP-deficient or TYROBP-overexpressing. Remarkably, constitutively TYROBP-deficient mice provided a model of genetic resilience to either of the defining proteinopathies of AD. Learning behavior and synaptic electrophysiological function were preserved at normal physiological levels even in the face of robust cerebral amyloidosis (in APP/PSEN1;Tyrobp
-/- mice) or tauopathy (in MAPTP301S ;Tyrobp-/- mice). A fundamental underpinning of the functional synaptic dysfunction associated with each proteotype was an accumulation of complement C1q. TYROBP deficiency prevented C1q accumulation associated with either proteinopathy. Based on these data, we speculate that TYROBP plays a key role in the microglial sensome and the emergence of the disease-associated microglia (DAM) phenotype. TYROBP may also play a key role in the loss of markers of synaptic integrity (e.g., synaptophysin-like immunoreactivity) that has long been held to be the feature of human AD molecular neuropathology that most closely correlates with concurrent clinical cognitive function., (© 2022. The Author(s).)- Published
- 2022
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40. Chronic neutropenia: how best to assess severity and approach management?
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Donadieu J, Frenz S, Merz L, Sicre De Fontbrune F, Rotulo GA, Beaupain B, Biosse-Duplan M, Audrain M, Croisille L, Ancliff P, Klein C, and Bellanné-Chantelot C
- Subjects
- Antibiotic Prophylaxis adverse effects, Child, Child, Preschool, Congenital Bone Marrow Failure Syndromes, Female, Granulocyte Colony-Stimulating Factor therapeutic use, Humans, Bacterial Infections, Neutropenia diagnosis, Neutropenia etiology, Neutropenia therapy
- Abstract
Introduction: Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management., Areas Covered: The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care., Expert Opinion: In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 10
6 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.- Published
- 2021
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41. Neonatal Screening for SCID: The French Experience.
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Audrain M and Thomas C
- Abstract
After it was demonstrated in 2005 that T cell receptor excision circle (TREC) quantification for dried blood spot (DBS) samples on Guthrie cards is an effective means of SCID screening and following several pilot studies, the practice was formally recommended in the US in 2010. More and more countries have adopted it since then. In France, before the health authorities could recommend adding SCID to the list of five diseases that were routinely screened for, feasibility and cost-effectiveness studies had to be conducted with a sufficiently large cohort of neonates. We carried out three such studies: The first sought to verify the effectiveness of the assay. The second, DEPISTREC, evaluated the feasibility of universal SCID screening in France and assessed the clinical benefit and economic advantage it would provide. Through the third study, NeoSKID, still under way and to continue until recommendations are issued, we have been offering SCID screening in the Pays de la Loire region of France. This review briefly describes routine newborn screening (NBS) and management of primary immunodeficiency diseases (PIDs) in France, and then considers the lessons from our studies and the status of SCID screening implementation within the country.
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- 2021
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42. Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice.
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Audrain M, Haure-Mirande JV, Mleczko J, Wang M, Griffin JK, St George-Hyslop PH, Fraser P, Zhang B, Gandy S, and Ehrlich ME
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- Alzheimer Disease genetics, Amyloid beta-Protein Precursor physiology, Amyloidosis prevention & control, Animals, Brain metabolism, Brain pathology, Disease Models, Animal, Humans, Mice, Mice, Knockout, Phosphorylation, Presenilin-1 physiology, Signal Transduction, tau Proteins metabolism, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease metabolism, Apolipoproteins E genetics, Membrane Glycoproteins genetics, Mice, Transgenic, Microglia metabolism, Receptors, Immunologic genetics
- Abstract
Introduction: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late-onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia., Methods: Using a novel transgenic mouse overexpressing TYROBP in microglia, we observed a decrease of the amyloid burden and an increase of TAU phosphorylation stoichiometry when crossed with APP/PSEN1 or MAPT
P301S mice, respectively. Characterization of these mice revealed Tyrobp-related modulation of apolipoprotein E (Apoe) transcription. We also showed that Tyrobp and Apoe mRNAs were increased in Trem2-null microglia recruited around either amyloid beta deposits or a cortical stab injury. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent., Conclusions: Our results provide evidence that TYROBP-APOE signaling does not require TREM2 and could be an initiating step in establishment of the disease-associated microglia (DAM) phenotype., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)- Published
- 2021
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43. miR155 regulation of behavior, neuropathology, and cortical transcriptomics in Alzheimer's disease.
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Readhead B, Haure-Mirande JV, Mastroeni D, Audrain M, Fanutza T, Kim SH, Blitzer RD, Gandy S, Dudley JT, and Ehrlich ME
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- Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Animals, Brain metabolism, Disease Models, Animal, Gene Regulatory Networks genetics, Humans, Mice, Transgenic, Nervous System Diseases pathology, Plaque, Amyloid pathology, Alzheimer Disease genetics, Brain pathology, MicroRNAs genetics, Transcriptome genetics
- Abstract
MicroRNAs are recognized as important regulators of many facets of physiological brain function while also being implicated in the pathogenesis of several neurological disorders. Dysregulation of miR155 is widely reported across a variety of neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. In previous work, we observed that experimentally validated miR155 gene targets were consistently enriched among genes identified as differentially expressed across multiple brain tissue and disease contexts. In particular, we found that human herpesvirus-6A (HHV-6A) suppressed miR155, recapitulating reports of miR155 inhibition by HHV-6A in infected T-cells, thyrocytes, and natural killer cells. In earlier studies, we also reported the effects of constitutive deletion of miR155 on accelerating the accumulation of Aβ deposits in 4-month-old APP/PSEN1 mice. Herein, we complete the cumulative characterization of transcriptomic, electrophysiological, neuropathological, and learning behavior profiles from 4-, 8- and 10-month-old WT and APP/PSEN1 mice in the absence or presence of miR155. We also integrated human post-mortem brain RNA-sequences from four independent AD consortium studies, together comprising 928 samples collected from six brain regions. We report that gene expression perturbations associated with miR155 deletion in mouse cortex are in aggregate observed to be concordant with AD-associated changes across these independent human late-onset AD (LOAD) data sets, supporting the relevance of our findings to human disease. LOAD has recently been formulated as the clinicopathological manifestation of a multiplex of genetic underpinnings and pathophysiological mechanisms. Our accumulated data are consistent with such a formulation, indicating that miR155 may be uniquely positioned at the intersection of at least four components of this LOAD "multiplex": (1) innate immune response pathways; (2) viral response gene networks; (3) synaptic pathology; and (4) proamyloidogenic pathways involving the amyloid β peptide (Aβ).
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- 2020
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44. Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease.
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Beckmann ND, Lin WJ, Wang M, Cohain AT, Charney AW, Wang P, Ma W, Wang YC, Jiang C, Audrain M, Comella PH, Fakira AK, Hariharan SP, Belbin GM, Girdhar K, Levey AI, Seyfried NT, Dammer EB, Duong D, Lah JJ, Haure-Mirande JV, Shackleton B, Fanutza T, Blitzer R, Kenny E, Zhu J, Haroutunian V, Katsel P, Gandy S, Tu Z, Ehrlich ME, Zhang B, Salton SR, and Schadt EE
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease pathology, Amyloid beta-Peptides metabolism, Animals, Datasets as Topic, Disease Models, Animal, Female, Gene Expression Profiling, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Male, Mice, Mice, Transgenic, Nerve Growth Factors genetics, Protein Interaction Mapping, Proteomics, Alzheimer Disease etiology, Brain pathology, Nerve Growth Factors metabolism, Protein Interaction Maps
- Abstract
Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.
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- 2020
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45. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice.
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El Gaamouch F, Audrain M, Lin WJ, Beckmann N, Jiang C, Hariharan S, Heeger PS, Schadt EE, Gandy S, Ehrlich ME, and Salton SR
- Subjects
- Alzheimer Disease metabolism, Animals, Cell Line, Disease Models, Animal, Humans, Mice, Mice, Transgenic, Signal Transduction physiology, Alzheimer Disease pathology, Microglia metabolism, Peptide Fragments metabolism, Receptors, Complement metabolism
- Abstract
Background: Multiomic studies by several groups in the NIH Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) identified VGF as a major driver of Alzheimer's disease (AD), also finding that reduced VGF levels correlate with mean amyloid plaque density, Clinical Dementia Rating (CDR) and Braak scores. VGF-derived peptide TLQP-21 activates the complement C3a receptor-1 (C3aR1), predominantly expressed in the brain on microglia. However, it is unclear how mouse or human TLQP-21, which are not identical, modulate microglial function and/or AD progression., Methods: We performed phagocytic/migration assays and RNA sequencing on BV2 microglial cells and primary microglia isolated from wild-type or C3aR1-null mice following treatment with TLQP-21 or C3a super agonist (C3aSA). Effects of intracerebroventricular TLQP-21 delivery were evaluated in 5xFAD mice, a mouse amyloidosis model of AD. Finally, the human HMC3 microglial cell line was treated with human TLQP-21 to determine whether specific peptide functions are conserved from mouse to human., Results: We demonstrate that TLQP-21 increases motility and phagocytic capacity in murine BV2 microglial cells, and in primary wild-type but not in C3aR1-null murine microglia, which under basal conditions have impaired phagocytic function compared to wild-type. RNA sequencing of primary microglia revealed overlapping transcriptomic changes induced by treatment with TLQP-21 or C3a super agonist (C3aSA). There were no transcriptomic changes in C3aR1-null or wild-type microglia exposed to the mutant peptide TLQP-R21A, which does not activate C3aR1. Most of the C3aSA- and TLQP-21-induced differentially expressed genes were linked to cell migration and proliferation. Intracerebroventricular TLQP-21 administration for 28 days via implanted osmotic pump resulted in a reduction of amyloid plaques and associated dystrophic neurites and restored expression of subsets of Alzheimer-associated microglial genes. Finally, we found that human TLQP-21 activates human microglia in a fashion similar to activation of murine microglia by mouse TLQP-21., Conclusions: These data provide molecular and functional evidence suggesting that mouse and human TLQP-21 modulate microglial function, with potential implications for the progression of AD-related neuropathology.
- Published
- 2020
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46. Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau.
- Author
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Audrain M, Haure-Mirande JV, Wang M, Kim SH, Fanutza T, Chakrabarty P, Fraser P, St George-Hyslop PH, Golde TE, Blitzer RD, Schadt EE, Zhang B, Ehrlich ME, and Gandy S
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing physiology, Alzheimer Disease genetics, Alzheimer Disease physiopathology, Amyloid beta-Protein Precursor metabolism, Animals, Animals, Genetically Modified, Brain metabolism, Complement C1q metabolism, Complement C1q physiology, Disease Models, Animal, Humans, Membrane Proteins genetics, Membrane Proteins metabolism, Membrane Proteins physiology, Mice, Mice, Knockout, Mice, Transgenic, Microglia metabolism, Phenotype, Phosphorylation, Plaque, Amyloid metabolism, Tauopathies genetics, tau Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Alzheimer Disease metabolism
- Abstract
TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPβ1, CR3) associated with Alzheimer's disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.e., hyperphosphorylation and increased tauopathy spreading) were unexpectedly increased in MAPT
P301S ;Tyrobp-/- mice despite the improved learning behavior and synaptic function relative to controls with normal levels of TYROBP. Notably, levels of complement cascade initiator C1q were reduced in MAPTP301S ;Tyrobp-/- mice, consistent with the prediction that C1q reduction exerts a neuroprotective effect. These observations suggest a model wherein TYROBP-KO-(knock-out)-associated reduction in C1q is associated with normalized learning behavior and electrophysiological properties in tauopathy model mice despite a paradoxical evolution of biomarker signatures usually associated with neurological decline.- Published
- 2019
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47. Clinical and economic aspects of newborn screening for severe combined immunodeficiency: DEPISTREC study results.
- Author
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Thomas C, Durand-Zaleski I, Frenkiel J, Mirallié S, Léger A, Cheillan D, Picard C, Mahlaoui N, Riche VP, Roussey M, Sébille V, Rabetrano H, Dert C, Fischer A, and Audrain M
- Subjects
- Costs and Cost Analysis, Dried Blood Spot Testing economics, Female, France, Humans, Infant, Infant, Newborn, Lymphocyte Count, Lymphopenia economics, Male, Receptors, Antigen, T-Cell immunology, Severe Combined Immunodeficiency economics, T-Lymphocytes immunology, Lymphopenia diagnosis, Neonatal Screening economics, Severe Combined Immunodeficiency diagnosis
- Abstract
Purpose: Severe combined immunodeficiency (SCID) refers to a group of genetic disorders characterized by greatly compromised cellular and humoral immunity. Children with SCID are asymptomatic at birth, but they die from infections within the first months of life if not treated. Quantification of T-cell receptor excision circles is an extremely sensitive screening method for detecting newborns who may have SCID.The goal of the DEPISTREC study was to evaluate the feasibility of nationwide newborn screening for severe T-cell lymphopenia in France as well as its economic and clinical utility., Methods: The test universally used for neonatal screening for SCID was the quantification of TRECs on Guthrie cards. We compared a group of 190,517 babies from 48 maternities across the country who underwent newborn SCID screening with a control group of 1.4 million babies out of whom 28 were diagnosed with SCID without such screening during the course of the study., Results: Within the screening group, 62 babies were found to be lymphopenic, including three with SCID. The cost of screening ranged from 4.7€ to €8.15 per newborn. The average 18-month cost was €257,574 vs €204,697 in the control group., Conclusions: In this large-scale study, we demonstrate that routine SCID screening is feasible and effective. This screening offers the additional benefit of aiding in the diagnosis of non-SCID lymphopenia. Economic evaluation allowed us to calculate the cost per test. Newborn screening may also prevent death by SCID before any curative treatment can be administered. The difference in cost between screened and control children could not be ascertained because of the very low numbers and death of one of the children tested., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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48. Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice.
- Author
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Souchet B, Audrain M, Billard JM, Dairou J, Fol R, Orefice NS, Tada S, Gu Y, Dufayet-Chaffaud G, Limanton E, Carreaux F, Bazureau JP, Alves S, Meijer L, Janel N, Braudeau J, and Cartier N
- Subjects
- Alzheimer Disease enzymology, Alzheimer Disease pathology, Animals, Hippocampus, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Organ Culture Techniques, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Dyrk Kinases, Alzheimer Disease genetics, Amyloid beta-Protein Precursor genetics, Phenotype, Presenilin-1 genetics, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics, Proteolysis
- Abstract
Recent evidences suggest the involvement of DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1 A) in Alzheimer's disease (AD). Here we showed that DYRK1A undergoes a proteolytic processing in AD patients hippocampus without consequences on its kinase activity. Resulting truncated forms accumulate in astrocytes and exhibit increased affinity towards STAT3ɑ, a regulator of inflammatory process. These findings were confirmed in APP/PS1 mice, an amyloid model of AD, suggesting that this DYRK1A cleavage is a consequence of the amyloid pathology. We identified in vitro the Leucettine L41 as a compound able to prevent DYRK1A proteolysis in both human and mouse protein extracts. We then showed that intraperitoneal injections of L41 in aged APP/PS1 mice inhibit STAT3ɑ phosphorylation and reduce pro-inflammatory cytokines levels (IL1- β, TNF-ɑ and IL-12) associated to an increased microglial recruitment around amyloid plaques and decreased amyloid-β plaque burden. Importantly, L41 treatment improved synaptic plasticity and rescued memory functions in APP/PS1 mice. Collectively, our results suggest that DYRK1A may contribute to AD pathology through its proteolytic process, reducing its kinase specificity. Further evaluation of inhibitors of DYRK1A truncation promises a new therapeutic approach for AD.
- Published
- 2019
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49. Correction: Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden.
- Author
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Haure-Mirande JV, Wang M, Audrain M, Fanutza T, Kim SH, Heja S, Readhead B, Dudley JT, Blitzer RD, Schadt EE, Zhang B, Gandy S, and Ehrlich ME
- Abstract
This article was originally published under standard licence, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.
- Published
- 2019
- Full Text
- View/download PDF
50. Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden.
- Author
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Haure-Mirande JV, Wang M, Audrain M, Fanutza T, Kim SH, Heja S, Readhead B, Dudley JT, Blitzer RD, Schadt EE, Zhang B, Gandy S, and Ehrlich ME
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Amyloid beta-Protein Precursor genetics, Amyloidosis genetics, Animals, Brain metabolism, Disease Models, Animal, Female, Gene Regulatory Networks, Humans, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Pathology, Molecular methods, Phenotype, Plaque, Amyloid pathology, Transcriptome, Adaptor Proteins, Signal Transducing deficiency, Alzheimer Disease metabolism, Amyloid beta-Peptides metabolism, Amyloidosis metabolism, Membrane Proteins deficiency
- Abstract
Integrative gene network approaches enable new avenues of exploration that implicate causal genes in sporadic late-onset Alzheimer's disease (LOAD) pathogenesis, thereby offering novel insights for drug-discovery programs. We previously constructed a probabilistic causal network model of sporadic LOAD and identified TYROBP/DAP12, encoding a microglial transmembrane signaling polypeptide and direct adapter of TREM2, as the most robust key driver gene in the network. Here, we show that absence of TYROBP/DAP12 in a mouse model of AD-type cerebral Aβ amyloidosis (APP
KM670/671NL /PSEN1Δexon9 ) recapitulates the expected network characteristics by normalizing the transcriptome of APP/PSEN1 mice and repressing the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia (DAM), including Trem2, complement (C1qa, C1qb, C1qc, and Itgax), Clec7a and Cst7. Importantly, we show that constitutive absence of TYROBP/DAP12 in the amyloidosis mouse model prevented appearance of the electrophysiological and learning behavior alterations associated with the phenotype of APPKM670/671NL /PSEN1Δexon9 mice. Our results suggest that TYROBP/DAP12 could represent a novel therapeutic target to slow, arrest, or prevent the development of sporadic LOAD. These data establish that the network pathology observed in postmortem human LOAD brain can be faithfully recapitulated in the brain of a genetically manipulated mouse. These data also validate our multiscale gene networks by demonstrating how the networks intersect with the standard neuropathological features of LOAD.- Published
- 2019
- Full Text
- View/download PDF
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