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Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid‐β (Aβ) oligomers

Background and Purpose Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio‐1911 in Aβ oligomer (AβO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's...

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Published in:British journal of pharmacology 2024-10, Vol.181 (20), p.4028-4049
Main Authors: Diniz, Luan Pereira, Morgado, Juliana, Bergamo Araujo, Ana Paula, Silva Antônio, Leticia Maria, Mota‐Araujo, Hannah Paola, Sena Murteira Pinheiro, Pedro, Sagrillo, Fernanda Savacini, Cesar, Gabriele Vargas, Ferreira, Sérgio T., Figueiredo, Cláudia Pinto, Manssour Fraga, Carlos Alberto, Gomes, Flávia Carvalho Alcantara
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container_issue 20
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container_title British journal of pharmacology
container_volume 181
creator Diniz, Luan Pereira
Morgado, Juliana
Bergamo Araujo, Ana Paula
Silva Antônio, Leticia Maria
Mota‐Araujo, Hannah Paola
Sena Murteira Pinheiro, Pedro
Sagrillo, Fernanda Savacini
Cesar, Gabriele Vargas
Ferreira, Sérgio T.
Figueiredo, Cláudia Pinto
Manssour Fraga, Carlos Alberto
Gomes, Flávia Carvalho Alcantara
description Background and Purpose Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio‐1911 in Aβ oligomer (AβO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). Experimental Approach Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AβO. Key Results LASSBio‐1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AβO‐triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio‐1911 improves behavioural performance and rescues synaptic and memory function in AβO‐infused mice. Conclusion and Implications These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD. ▪
doi_str_mv 10.1111/bph.16439
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We have evaluated the therapeutic potential of the new iHDAC LASSBio‐1911 in Aβ oligomer (AβO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). Experimental Approach Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AβO. Key Results LASSBio‐1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AβO‐triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio‐1911 improves behavioural performance and rescues synaptic and memory function in AβO‐infused mice. 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Conclusion and Implications These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD. ▪</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>38936407</pmid><doi>10.1111/bph.16439</doi><tpages>22</tpages><orcidid>https://orcid.org/0000-0003-2966-0638</orcidid><orcidid>https://orcid.org/0000-0003-4148-4243</orcidid></addata></record>
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subjects Alzheimer's disease
Amyloid beta-Peptides - metabolism
Amyloid beta-Peptides - toxicity
Animal models
Animals
astrocyte
Astrocytes
Astrocytes - drug effects
Astrocytes - metabolism
Cells, Cultured
Cognitive ability
Cognitive Dysfunction - chemically induced
Cognitive Dysfunction - drug therapy
Cognitive Dysfunction - metabolism
Drug development
Flow cytometry
Histone deacetylase
histone deacetylase inhibitor
Histone Deacetylase Inhibitors - pharmacology
Immunofluorescence
Male
Mice
Mice, Inbred C57BL
multitarget drugs
Neurodegenerative diseases
neuroinflammation
Neuroprotection
Neuroprotective Agents - administration & dosage
Neuroprotective Agents - pharmacology
Oligomers
Phenotypes
reactivity
Synapses
Synapses - drug effects
Synapses - metabolism
Synaptic density
Toxicity
Western blotting
β-Amyloid
title Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid‐β (Aβ) oligomers
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