Evaluating the impact of age and treatment on neuroinflammation-related proteins in mouse models of proteinopathies

Abstract

Neuroinflammation plays a key role in Alzheimer's disease (AD), but the actions of microglial mediators may vary across stages of amyloid-beta (Aβ) pathology. While drugs targeting brain immune responses are advancing to clinical trials, biomarkers to monitor their effects are lacking. This study investigated proteins expressed by activated microglia in three mouse models of Aβ pathology and α-synuclein, both during disease progression and after treatment, to evaluate their potential as in vivo biomarkers. Immunofluorescent staining was performed on cortical sections from App^NL-G-F, tg-ArcSwe, and wild-type (WT) mice. TREM2, Axl, galectin-3, Aβ, and cytokines were measured by immunoassays in brain homogenates from WT, App^NL-G-F, tg-ArcSwe, and tg-UppSwe mice across four age groups and from mice subjected to three treatment strategies targeting Aβ (beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor NB-360 and antibody RmAb158) or α-synuclein (antibody RmAb38E2). TREM2 and Axl colocalized with Iba1 and Aβ in App^NL-G-F and tg-ArcSwe mice, with age-dependent increases observed in both models but not in tg-UppSwe. The lectin galectin-3 increased with age across all genotypes, including WT. Aβ correlated with elevated TREM2, Axl, and Galectin-3. Two months of BACE1-inhibition reduced TREM2, Axl, and galectin-3 in tg-ArcSwe mice and TREM2 and Axl in App^NL-G-F mice. In summary, microglial TREM2, Axl, and galectin-3 are promising biomarkers for tracking AD-related neuroinflammation. Microglial interactions with Aβ likely influence the outcomes of Aβ-targeting therapies, and characterizing their dynamic states will inform the development of diagnostic tools and treatments relying on microglial activation to alleviate pathologies associated with neurodegenerative diseases.