| First Author | Jagadeesan N | Year | 2024 |
| Journal | J Transl Med | Volume | 22 |
| Issue | 1 | Pages | 291 |
| PubMed ID | 38500108 | Mgi Jnum | J:350688 |
| Mgi Id | MGI:7664333 | Doi | 10.1186/s12967-024-05008-x |
| Citation | Jagadeesan N, et al. (2024) Modulation of hippocampal protein expression by a brain penetrant biologic TNF-alpha inhibitor in the 3xTg Alzheimer's disease mice. J Transl Med 22(1):291 |
| abstractText | BACKGROUND: Biologic TNF-alpha inhibitors (bTNFIs) can block cerebral TNF-alpha 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-alpha receptor (TNFR), which can bind to and sequester TNF-alpha, 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 Abeta, 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 Abeta-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 Abeta 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 Abeta plaques and increased Abeta-associated microglia around larger Abeta deposits in the 3xTg-AD mice. Further, TfRMAb-TNFR increased mature Abeta plaque-associated microglial TREM2 in 3xTg-AD mice. CONCLUSION: Overall, despite the low visual Abeta 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. |
