Modulating innate immune activation states impacts the efficacy of specific Aβ immunotherapy
| Autor: | Dennis W. Dickson, Baxter Bramblett, Karen N. McFarland, Nathan D. Price, Mariet Allen, Todd E. Golde, Nilufer Ertekin-Taner, Cory C. Funk, Xue Wang, Hong-Dong Li, Xufei Liu, Max Robinson, Pedro E. Cruz, Daniel Ryu, Paramita Chakrabarty, Yona Levites, Veronica O’Neal, Thomas B. Ladd, Minerva M. Carrasquillo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Amyloid Transgene medicine.medical_treatment Priming (immunology) Inflammation Mice Transgenic Biology Adenoassociated virus Il6 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Alzheimer Disease RNA seq medicine Animals Humans RC346-429 Receptor Molecular Biology Il10 Temporal cortex Innate immune system Amyloid beta-Peptides Interleukin-6 RC952-954.6 Immunization Passive Antibodies Monoclonal Immunotherapy Immunity Innate Interleukin-10 030104 developmental biology Gliosis Geriatrics Immunology Neurology. Diseases of the nervous system Neurology (clinical) medicine.symptom Alzheimer’s disease 030217 neurology & neurosurgery Research Article |
| Zdroj: | Molecular Neurodegeneration Molecular Neurodegeneration, Vol 16, Iss 1, Pp 1-13 (2021) |
| ISSN: | 1750-1326 |
| Popis: | Introduction Passive immunotherapies targeting Aβ continue to be evaluated as Alzheimer’s disease (AD) therapeutics, but there remains debate over the mechanisms by which these immunotherapies work. Besides the amount of preexisting Aβ deposition and the type of deposit (compact or diffuse), there is little data concerning what factors, independent of those intrinsic to the antibody, might influence efficacy. Here we (i) explored how constitutive priming of the underlying innate activation states by Il10 and Il6 might influence passive Aβ immunotherapy and (ii) evaluated transcriptomic data generated in the AMP-AD initiative to inform how these two cytokines and their receptors’ mRNA levels are altered in human AD and an APP mouse model. Methods rAAV2/1 encoding EGFP, Il6 or Il10 were delivered by somatic brain transgenesis to neonatal (P0) TgCRND8 APP mice. Then, at 2 months of age, the mice were treated bi-weekly with a high-affinity anti-Aβ1–16 mAb5 monoclonal antibody or control mouse IgG until 6 months of age. rAAV mediated transgene expression, amyloid accumulation, Aβ levels and gliosis were assessed. Extensive transcriptomic data was used to evaluate the mRNA expression levels of IL10 and IL6 and their receptors in the postmortem human AD temporal cortex and in the brains of TgCRND8 mice, the later at multiple ages. Results Priming TgCRND8 mice with Il10 increases Aβ loads and blocks efficacy of subsequent mAb5 passive immunotherapy, whereas priming with Il6 priming reduces Aβ loads by itself and subsequent Aβ immunotherapy shows only a slightly additive effect. Transcriptomic data shows that (i) there are significant increases in the mRNA levels of Il6 and Il10 receptors in the TgCRND8 mouse model and temporal cortex of humans with AD and (ii) there is a great deal of variance in individual mouse brain and the human temporal cortex of these interleukins and their receptors. Conclusions The underlying immune activation state can markedly affect the efficacy of passive Aβ immunotherapy. These results have important implications for ongoing human AD immunotherapy trials, as they indicate that underlying immune activation states within the brain, which may be highly variable, may influence the ability for passive immunotherapy to alter Aβ deposition. |
| Databáze: | OpenAIRE |
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