Document Type
Article
Publication Date
4-7-2023
Abstract
Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer’s disease (AD) but has limited blood–brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; n = 10); every two or three days on alternate weeks for 8 weeks. Age-matched, saline-treated, wildtype littermates (WT-Saline; n = 12) were injected using the same protocol. After 8 weeks, locomotion, hyperactivity, and anxiety were assessed via the open-field test, and brains were harvested and sectioned. Cerebral cortex, hippocampus, amygdala, and entorhinal cortex sections were analyzed for phospho-tau (AT8) and microgliosis (Iba1). Hippocampal cellular density (H&E) was also assessed. PS19-Saline mice were hyperactive and less anxious compared to WT-Saline mice, and these behavioral phenotypes were significantly reduced in the PS19-cTfRMAb-EPO mice compared to the PS19-Saline mice. cTfRMAb-EPO significantly reduced AT8 load by ≥50% in all of the brain regions analyzed and microgliosis in the entorhinal cortex and amygdala compared to the PS19-Saline mice. Hippocampal pyramidal and granule cell layer density did not differ significantly between the PS19-cTfRMAb-EPO and PS19-Saline mice. This proof-of-concept study demonstrates the therapeutic effects of the BBB-penetrating cTfRMAb-EPO in PS19 mice.
Recommended Citation
Yang, J.; Ou,W.; Jagadeesan, N.; Simanauskaite, J.; Sun, J.; Castellanos, D.; Cribbs, D.H.; Sumbria, R.K. The Effects of a Blood–Brain Barrier Penetrating Erythropoietin in a Mouse Model of Tauopathy. Pharmaceuticals 2023, 16, 558. https://doi.org/10.3390/ph16040558
Supplemental materials. Figure S1: (A) Schematic of the study design. (B) Weekly weights of the mice over the course of the 8-week treatment; Figure S2: (A) Total plasma tau in the cTfRMAb-EPO-treated mice following 8 weeks of treatment of six-month-old PS19 mice. (B) AT8-positive phospho-tau (Ser202, Thr205) in the PS19-Saline- and PS19-cTfRMAb-EPO-treated mice in whole-brain homogenates using Western blotting. (C) Correlation between the overall brain AT8-positive area and total plasma tau; Video S1: Open-field video for a representative WT mouse; Video S2: Open-field video for a representative PS19-Saline mouse; Video S3: Open-field video for a representative PS19-cTfRMAb-EPO mouse.
Copyright
The authors
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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Animal Experimentation and Research Commons, Medicinal and Pharmaceutical Chemistry Commons, Nervous System Diseases Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Therapeutics Commons
Comments
This article was originally published in Pharmaceuticals, volume 16, in 2023. https://doi.org/10.3390/ph16040558