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

• 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
• Format: Article
• Language: English
• 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
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.16439

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. ▪