Intravenous chaperone treatment of late-stage Alzheimer's disease (AD) mouse model affects amyloid plaque load, reactive gliosis and AD related genes

Treatment strategies that are efficient against established Alzheimer's disease (AD) are needed. BRICHOS is a molecular chaperone domain that prevents amyloid fibril formation and associated cellular toxicity. In this study, we treated an AD mouse model seven months after pathology onset, using intravenous administration of recombinant human (rh) Bri2 BRICHOS R221E. Two injections of rh Bri2 BRICHOS R221E per week for three months in AD mice reduced amyloid b (Ab) burden, and mitigated astro- and microgliosis, as determined by glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) immunohistochemistry. Sequencing of RNA from cortical microglia cells showed that BRICHOS treatment normalized expression of identified plaque-induced genes in mice and humans, including clusterin and GFAP. Rh Bri2 BRICHOS R221E passed the blood-brain barrier (BBB) in age-matched wildtype mice as efficiently as in the AD mice, but then had no effect on measures of AD-like pathology, and mainly affected the expression of genes involved in cellular shape and movement. These results indicate a potential of rh Bri2 BRICHOS against advanced AD and underscore the ability of BRICHOS to target amyloid-induced pathology. Overall design: To investigat the effects of rh Bri2 BRICHOS treatment on microglial activation, we isolated cortical microglial cells from three mice from each of the four treatment groups, i.e. WT and AppNL-G-F mice treated with either PBS (veh) or rh Bri2 BRICHOS R221E, and performed bulk mRNA sequencing.