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Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models
We have previously shown that histone deacetylase (HDAC) inhibition and cranial radiotherapy (RT) independently improve molecular and behavioral Alzheimer’s disease (AD)-like phenotypes. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low-dose combinati...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10293392/ https://www.ncbi.nlm.nih.gov/pubmed/37171575 http://dx.doi.org/10.1007/s12035-023-03373-0 |
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author | Ricciardi, Natalie R. Modarresi, Farzaneh Lohse, Ines Andrade, Nadja S. Newman, Ian R. Brown, Jonathan M. Borja, Caroline Marples, Brian Wahlestedt, Claes R. Volmar, Claude-Henry |
author_facet | Ricciardi, Natalie R. Modarresi, Farzaneh Lohse, Ines Andrade, Nadja S. Newman, Ian R. Brown, Jonathan M. Borja, Caroline Marples, Brian Wahlestedt, Claes R. Volmar, Claude-Henry |
author_sort | Ricciardi, Natalie R. |
collection | PubMed |
description | We have previously shown that histone deacetylase (HDAC) inhibition and cranial radiotherapy (RT) independently improve molecular and behavioral Alzheimer’s disease (AD)-like phenotypes. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low-dose combination therapy (LDCT) to maximize disease modification (reduce neuroinflammation and amyloidogenic APP processing, increase neurotrophic gene expression) while minimizing the potential for treatment-associated side effects. LDCT consisted of daily administration of the HDAC3 inhibitor RGFP966 and/or bi-weekly cranial x-irradiation. Amyloid-beta precursor protein (APP) processing and innate immune response to LDCT were assessed in vitro and in vivo using human and murine cell models and 3xTg-AD mice. After 2 months of LDCT in mice, behavioral analyses as well as expression and modification of key AD-related targets (Aβ, tau, Csf1r, Bdnf, etc.) were assessed in the hippocampus (HIP) and prefrontal cortex (PFC). LDCT induced a tolerant, anti-inflammatory innate immune response in microglia and increased non-amyloidogenic APP processing in vitro. Both RT and LDCT improved the rate of learning and spatial memory in the Barnes maze test. LDCT induced a unique anti-AD HIP gene expression profile that included upregulation of neurotrophic genes and downregulation of inflammation-related genes. RT lowered HIP Aβ(42/40) ratio and Bace1 protein, while LDCT lowered PFC p-tau181 and HIP Bace1 levels. Our study supports the rationale for combining complementary therapeutic approaches at low doses to target multifactorial AD pathology synergistically. Namely, LDCT with RGFP966 and cranial RT shows disease-modifying potential against a wide range of AD-related hallmarks. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03373-0. |
format | Online Article Text |
id | pubmed-10293392 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-102933922023-06-28 Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models Ricciardi, Natalie R. Modarresi, Farzaneh Lohse, Ines Andrade, Nadja S. Newman, Ian R. Brown, Jonathan M. Borja, Caroline Marples, Brian Wahlestedt, Claes R. Volmar, Claude-Henry Mol Neurobiol Article We have previously shown that histone deacetylase (HDAC) inhibition and cranial radiotherapy (RT) independently improve molecular and behavioral Alzheimer’s disease (AD)-like phenotypes. In the present study, we investigate the synergistic potential of using both RT and HDACi as a low-dose combination therapy (LDCT) to maximize disease modification (reduce neuroinflammation and amyloidogenic APP processing, increase neurotrophic gene expression) while minimizing the potential for treatment-associated side effects. LDCT consisted of daily administration of the HDAC3 inhibitor RGFP966 and/or bi-weekly cranial x-irradiation. Amyloid-beta precursor protein (APP) processing and innate immune response to LDCT were assessed in vitro and in vivo using human and murine cell models and 3xTg-AD mice. After 2 months of LDCT in mice, behavioral analyses as well as expression and modification of key AD-related targets (Aβ, tau, Csf1r, Bdnf, etc.) were assessed in the hippocampus (HIP) and prefrontal cortex (PFC). LDCT induced a tolerant, anti-inflammatory innate immune response in microglia and increased non-amyloidogenic APP processing in vitro. Both RT and LDCT improved the rate of learning and spatial memory in the Barnes maze test. LDCT induced a unique anti-AD HIP gene expression profile that included upregulation of neurotrophic genes and downregulation of inflammation-related genes. RT lowered HIP Aβ(42/40) ratio and Bace1 protein, while LDCT lowered PFC p-tau181 and HIP Bace1 levels. Our study supports the rationale for combining complementary therapeutic approaches at low doses to target multifactorial AD pathology synergistically. Namely, LDCT with RGFP966 and cranial RT shows disease-modifying potential against a wide range of AD-related hallmarks. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-023-03373-0. Springer US 2023-05-12 2023 /pmc/articles/PMC10293392/ /pubmed/37171575 http://dx.doi.org/10.1007/s12035-023-03373-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ricciardi, Natalie R. Modarresi, Farzaneh Lohse, Ines Andrade, Nadja S. Newman, Ian R. Brown, Jonathan M. Borja, Caroline Marples, Brian Wahlestedt, Claes R. Volmar, Claude-Henry Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models |
title | Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models |
title_full | Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models |
title_fullStr | Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models |
title_full_unstemmed | Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models |
title_short | Investigating the Synergistic Potential of Low-Dose HDAC3 Inhibition and Radiotherapy in Alzheimer’s Disease Models |
title_sort | investigating the synergistic potential of low-dose hdac3 inhibition and radiotherapy in alzheimer’s disease models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10293392/ https://www.ncbi.nlm.nih.gov/pubmed/37171575 http://dx.doi.org/10.1007/s12035-023-03373-0 |
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