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Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice

Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain...

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Autores principales: Ou, Weijun, Ohno, Yuu, Yang, Joshua, Chandrashekar, Devaraj V., Abdullah, Tamara, Sun, Jiahong, Murphy, Riley, Roules, Chuli, Jagadeesan, Nataraj, Cribbs, David H., Sumbria, Rachita K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612380/
https://www.ncbi.nlm.nih.gov/pubmed/36297637
http://dx.doi.org/10.3390/pharmaceutics14102200
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author Ou, Weijun
Ohno, Yuu
Yang, Joshua
Chandrashekar, Devaraj V.
Abdullah, Tamara
Sun, Jiahong
Murphy, Riley
Roules, Chuli
Jagadeesan, Nataraj
Cribbs, David H.
Sumbria, Rachita K.
author_facet Ou, Weijun
Ohno, Yuu
Yang, Joshua
Chandrashekar, Devaraj V.
Abdullah, Tamara
Sun, Jiahong
Murphy, Riley
Roules, Chuli
Jagadeesan, Nataraj
Cribbs, David H.
Sumbria, Rachita K.
author_sort Ou, Weijun
collection PubMed
description Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood–brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aβ) 1-42, soluble-oligomeric Aβ, and microgliosis; however, only TfRMAb-TNFR reduced Aβ peptides, Thioflavin-S-positive Aβ plaques, and insoluble-oligomeric Aβ and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice.
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spelling pubmed-96123802022-10-28 Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice Ou, Weijun Ohno, Yuu Yang, Joshua Chandrashekar, Devaraj V. Abdullah, Tamara Sun, Jiahong Murphy, Riley Roules, Chuli Jagadeesan, Nataraj Cribbs, David H. Sumbria, Rachita K. Pharmaceutics Article Tumor necrosis factor alpha (TNF-α) plays a vital role in Alzheimer’s disease (AD) pathology, and TNF-α inhibitors (TNFIs) modulate AD pathology. We fused the TNF-α receptor (TNFR), a biologic TNFI that sequesters TNF-α, to a transferrin receptor antibody (TfRMAb) to deliver the TNFI into the brain across the blood–brain barrier (BBB). TfRMAb-TNFR was protective in 6-month-old transgenic APP/PS1 mice in our previous work. However, the effects and safety following delayed chronic TfRMAb-TNFR treatment are unknown. Herein, we initiated the treatment when the male APP/PS1 mice were 10.7 months old (delayed treatment). Mice were injected intraperitoneally with saline, TfRMAb-TNFR, etanercept (non-BBB-penetrating TNFI), or TfRMAb for ten weeks. Biologic TNFIs did not alter hematology indices or tissue iron homeostasis; however, TfRMAb altered hematology indices, increased splenic iron transporter expression, and increased spleen and liver iron. TfRMAb-TNFR and etanercept reduced brain insoluble-amyloid beta (Aβ) 1-42, soluble-oligomeric Aβ, and microgliosis; however, only TfRMAb-TNFR reduced Aβ peptides, Thioflavin-S-positive Aβ plaques, and insoluble-oligomeric Aβ and increased plaque-associated phagocytic microglia. Accordingly, TfRMAb-TNFR improved spatial reference memory and increased BBB-tight junction protein expression, whereas etanercept did not. Overall, despite delayed treatment, TfRMAb-TNFR resulted in a better therapeutic response than etanercept without any TfRMAb-related hematology- or iron-dysregulation in aged APP/PS1 mice. MDPI 2022-10-16 /pmc/articles/PMC9612380/ /pubmed/36297637 http://dx.doi.org/10.3390/pharmaceutics14102200 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ou, Weijun
Ohno, Yuu
Yang, Joshua
Chandrashekar, Devaraj V.
Abdullah, Tamara
Sun, Jiahong
Murphy, Riley
Roules, Chuli
Jagadeesan, Nataraj
Cribbs, David H.
Sumbria, Rachita K.
Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice
title Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice
title_full Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice
title_fullStr Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice
title_full_unstemmed Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice
title_short Efficacy and Safety of a Brain-Penetrant Biologic TNF-α Inhibitor in Aged APP/PS1 Mice
title_sort efficacy and safety of a brain-penetrant biologic tnf-α inhibitor in aged app/ps1 mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612380/
https://www.ncbi.nlm.nih.gov/pubmed/36297637
http://dx.doi.org/10.3390/pharmaceutics14102200
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