Abstract
Attempts to treat Alzheimer's disease with immunotherapy against the β-amyloid (Aβ) peptide or with enzyme inhibitors to reduce Aβ production have not yet resulted in effective treatment, suggesting that alternative strategies may be useful. Here we explore the possibility of targeting the toxicity associated with Aβ aggregation by using the recombinant human (rh) Bri2 BRICHOS chaperone domain, mutated to act selectively against Aβ42 oligomer generation and neurotoxicity in vitro. We find that treatment of Aβ precursor protein (App) knockin mice with repeated intravenous injections of rh Bri2 BRICHOS R221E, from an age close to the start of development of Alzheimer's disease-like pathology, improves recognition and working memory, as assessed using novel object recognition and Y maze tests, and reduces Aβ plaque deposition and activation of astrocytes and microglia. When treatment was started about 4 months after Alzheimer's disease-like pathology was already established, memory improvement was not detected, but Aβ plaque deposition and gliosis were reduced, and substantially reduced astrocyte accumulation in the vicinity of Aβ plaques was observed. The degrees of treatment effects observed in the App knockin mouse models apparently correlate with the amounts of Bri2 BRICHOS detected in brain sections after the end of the treatment period.