Intravenous treatment with a molecular chaperone designed against ß-amyloid toxicity improves Alzheimer's disease pathology in mouse models.

ABSTRACT

Attempts to treat Alzheimer's disease with immunotherapy against the ß-amyloid (Aß) peptide or with enzyme inhibitors to reduce Aß 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 Aß aggregation by using the recombinant human (rh) Bri2 BRICHOS chaperone domain, mutated to act selectively against Aß42 oligomer generation and neurotoxicity in vitro. We find that treatment of Aß 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 Aß 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 Aß plaque deposition and gliosis were reduced, and substantially reduced astrocyte accumulation in the vicinity of Aß 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.