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.
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.
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