Astrocytic reactivity and amyloid load are reduced in a sex-dependent manner in a mouse model of amyloid pathology following protease-activated receptor 2 activation

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Edwards, Nicole and Sakata, Shuzo and McConnell, Gail and Bushell, Trevor (2026) Astrocytic reactivity and amyloid load are reduced in a sex-dependent manner in a mouse model of amyloid pathology following protease-activated receptor 2 activation. Neuropharmacology, 297. 111010. ISSN 0028-3908 (https://doi.org/10.1016/j.neuropharm.2026.111010)

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Abstract

Alzheimer’s disease is a leading cause of death, but current treatments are limited in their use and primarily offer symptomatic relief. Recent developments targeting amyloid plaques have given some hope, but their true value remains equivocal. Hence, alternative therapeutic targets are required with neuroinflammation, particularly glial cells, been a recent area of interest. Indeed, there has been intense research into the role of reactive astrocytes in neurodegenerative diseases with several studies indicating that reducing their reactivity is beneficial in animal models of disease. Building on our previous work using the blood brain barrier permeable protease-activated receptor 2 (PAR2) activator, AC264613 (AC), we investigate the consequence of AC administration on mouse behaviour, astrocytic reactivity and amyloid plaque load in the 5xFAD mouse model of amyloid pathology. Our data reveal similar behavioural changes in both 5xFAD- and 5xFAD+ mice that are sex-independent. However, AC reduces both GFAP and C3 expression levels, markers for astrocyte reactivity, in female but not male 5xFAD+ mice. In contrast, AC did not affect Iba1 and CD68 expression levels, markers for microglial activation and function, in mice of either sex. Significantly, AC reduced amyloid plaque load only in female 5xFAD+ mice similar to that seen with astrocyte reactivity. These data reveal that PAR2 activation can reduce astrocyte reactivity and amyloid plaque load in 5xFAD+ mice. Our findings add further weight to the proposal that targeting astrocyte reactivity to reduce neuroinflammation in neurodegenerative disorders, in this case using PAR2 activation, may be a viable therapeutic strategy.

ORCID iDs

Edwards, Nicole ORCID logoORCID: https://orcid.org/0009-0007-1590-0545, Sakata, Shuzo ORCID logoORCID: https://orcid.org/0000-0001-6796-411X, McConnell, Gail ORCID logoORCID: https://orcid.org/0000-0002-7213-0686 and Bushell, Trevor ORCID logoORCID: https://orcid.org/0000-0003-4145-9670;
CORE (COnnecting REpositories)