دورية أكاديمية
Modulation of hippocampal protein expression by a brain penetrant biologic TNF-α inhibitor in the 3xTg Alzheimer's disease mice.
العنوان: | Modulation of hippocampal protein expression by a brain penetrant biologic TNF-α inhibitor in the 3xTg Alzheimer's disease mice. |
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المؤلفون: | Jagadeesan N; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA., Roules GC; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA., Chandrashekar DV; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA., Yang J; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA., Kolluru S; Rancho Cucamonga High School, 11801 Lark Dr, Rancho Cucamonga, CA, 91701, USA., Sumbria RK; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. sumbria@chapman.edu.; Department of Neurology, University of California, Irvine, CA, 92697, USA. sumbria@chapman.edu. |
المصدر: | Journal of translational medicine [J Transl Med] 2024 Mar 18; Vol. 22 (1), pp. 291. Date of Electronic Publication: 2024 Mar 18. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: BioMed Central Country of Publication: England NLM ID: 101190741 Publication Model: Electronic Cited Medium: Internet ISSN: 1479-5876 (Electronic) Linking ISSN: 14795876 NLM ISO Abbreviation: J Transl Med Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [London] : BioMed Central, 2003- |
مواضيع طبية MeSH: | Alzheimer Disease*/drug therapy , Amyloidosis*/metabolism , Amyloidosis*/pathology , Biological Products*/metabolism, Mice ; Female ; Animals ; Tumor Necrosis Factor-alpha/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Neuroinflammatory Diseases ; Mice, Transgenic ; Brain/pathology ; Hippocampus/metabolism ; Hippocampus/pathology ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology ; Antibodies/metabolism ; Disease Models, Animal |
مستخلص: | Background: Biologic TNF-α inhibitors (bTNFIs) can block cerebral TNF-α in Alzheimer's disease (AD) if these macromolecules can cross the blood-brain barrier (BBB). Thus, a model bTNFI, the extracellular domain of type II TNF-α receptor (TNFR), which can bind to and sequester TNF-α, was fused with a mouse transferrin receptor antibody (TfRMAb) to enable brain delivery via BBB TfR-mediated transcytosis. Previously, we found TfRMAb-TNFR to be protective in a mouse model of amyloidosis (APP/PS1) and tauopathy (PS19), and herein we investigated its effects in mice that combine both amyloidosis and tauopathy (3xTg-AD). Methods: Eight-month-old female 3xTg-AD mice were injected intraperitoneally with saline (n = 11) or TfRMAb-TNFR (3 mg/kg; n = 11) three days per week for 12 weeks. Age-matched wild-type (WT) mice (n = 9) were treated similarly with saline. Brains were processed for immunostaining and high-resolution multiplex NanoString GeoMx spatial proteomics. Results: We observed regional differences in proteins relevant to Aβ, tau, and neuroinflammation in the hippocampus of 3xTg-AD mice compared with WT mice. From 64 target proteins studied using spatial proteomics, a comparison of the Aβ-plaque bearing vs. plaque-free regions in the 3xTg-AD mice yielded 39 differentially expressed proteins (DEP) largely related to neuroinflammation (39% of DEP) and Aβ and tau pathology combined (31% of DEP). Hippocampal spatial proteomics revealed that the majority of the proteins modulated by TfRMAb-TNFR in the 3xTg-AD mice were relevant to microglial function (⁓ 33%). TfRMAb-TNFR significantly reduced mature Aβ plaques and increased Aβ-associated microglia around larger Aβ deposits in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature Aβ plaque-associated microglial TREM2 in 3xTg-AD mice. Conclusion: Overall, despite the low visual Aβ load in the 11-month-old female 3xTg-AD mice, our results highlight region-specific AD-relevant DEP in the hippocampus of these mice. Chronic TfRMAb-TNFR dosing modulated several DEP involved in AD pathology and showed a largely microglia-centric mechanism of action in the 3xTg-AD mice. (© 2024. The Author(s).) |
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معلومات مُعتمدة: | R01 AG062840 United States AG NIA NIH HHS; R01AG072896 United States AG NIA NIH HHS; R01AG062840 United States AG NIA NIH HHS |
فهرسة مساهمة: | Keywords: 3xTg; Alzheimer’s disease; Amyloid beta; Biologic TNF-α inhibitor; Spatial proteomics; Tau; Transferrin receptor antibody |
المشرفين على المادة: | 0 (Tumor Necrosis Factor-alpha) 0 (Amyloid beta-Protein Precursor) 0 (Antibodies) 0 (Biological Products) |
تواريخ الأحداث: | Date Created: 20240319 Date Completed: 20240320 Latest Revision: 20240807 |
رمز التحديث: | 20240807 |
مُعرف محوري في PubMed: | PMC10946165 |
DOI: | 10.1186/s12967-024-05008-x |
PMID: | 38500108 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1479-5876 |
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DOI: | 10.1186/s12967-024-05008-x |