PMID- 34972522 OWN - NLM STAT- MEDLINE DCOM- 20220324 LR - 20220324 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 18 IP - 1 DP - 2021 Dec 31 TI - Biologic TNF-alpha inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy. PG - 312 LID - 10.1186/s12974-021-02332-7 [doi] LID - 312 AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a central role in Alzheimer's disease (AD) pathology, making biologic TNF-alpha inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Abeta deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Abeta-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood-brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-alpha receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. METHODS: Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. RESULTS: Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. CONCLUSION: Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy. CI - (c) 2021. The Author(s). FAU - Ou, Weijun AU - Ou W AD - Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. FAU - Yang, Joshua AU - Yang J AD - Henry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA. FAU - Simanauskaite, Juste AU - Simanauskaite J AD - Department of Neuroscience, Pomona College, Claremont, CA, 91711, USA. FAU - Choi, Matthew AU - Choi M AD - Keck Science Department, Claremont McKenna College, Claremont, CA, 91711, USA. FAU - Castellanos, Demi M AU - Castellanos DM AD - Henry E. Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, CA, 91711, USA. FAU - Chang, Rudy AU - Chang R AD - Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. FAU - Sun, Jiahong AU - Sun J AD - Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. FAU - Jagadeesan, Nataraj AU - Jagadeesan N AD - Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. FAU - Parfitt, Karen D AU - Parfitt KD AD - Department of Neuroscience, Pomona College, Claremont, CA, 91711, USA. FAU - Cribbs, David H AU - Cribbs DH AD - MIND Institute, University of California, Irvine, CA, 92697, USA. FAU - Sumbria, Rachita K AU - Sumbria RK AUID- ORCID: 0000-0002-7459-0723 AD - Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, 92618, USA. sumbria@chapman.edu. AD - Department of Neurology, University of California, Irvine, CA, 92868, USA. sumbria@chapman.edu. LA - eng GR - R01 AG062840/AG/NIA NIH HHS/United States GR - R01AG062840/AG/NIA NIH HHS/United States PT - Journal Article DEP - 20211231 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, mouse) RN - 0 (Mapt protein, mouse) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (tau Proteins) RN - OP401G7OJC (Etanercept) SB - IM MH - Animals MH - Disks Large Homolog 4 Protein/biosynthesis/genetics MH - Etanercept/pharmacokinetics/pharmacology MH - Female MH - Gliosis/*prevention & control MH - Hippocampus/pathology MH - Humans MH - Hyperkinesis MH - Male MH - Mice MH - Mice, Transgenic MH - Neurons/*pathology MH - Phosphorylation MH - Receptors, Tumor Necrosis Factor/antagonists & inhibitors MH - Tauopathies/genetics/*pathology MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors MH - tau Proteins/*antagonists & inhibitors/genetics/metabolism PMC - PMC8719395 OTO - NOTNLM OT - Alzheimer's disease OT - Biologic TNF-alpha inhibitor OT - Blood-brain barrier OT - Microgliosis OT - Molecular Trojan Horse OT - Tau OT - Transferrin receptor COIS- The authors declare that they have no competing interests. EDAT- 2022/01/02 06:00 MHDA- 2022/03/25 06:00 PMCR- 2021/12/31 CRDT- 2022/01/01 05:10 PHST- 2021/05/09 00:00 [received] PHST- 2021/11/26 00:00 [accepted] PHST- 2022/01/01 05:10 [entrez] PHST- 2022/01/02 06:00 [pubmed] PHST- 2022/03/25 06:00 [medline] PHST- 2021/12/31 00:00 [pmc-release] AID - 10.1186/s12974-021-02332-7 [pii] AID - 2332 [pii] AID - 10.1186/s12974-021-02332-7 [doi] PST - epublish SO - J Neuroinflammation. 2021 Dec 31;18(1):312. doi: 10.1186/s12974-021-02332-7.