Chronic intranasal treatment with an anti-Aß(30-42) scFv antibody ameliorates amyloid pathology in a transgenic mouse model of Alzheimer's disease.

ABSTRACT

Amyloid-beta peptide (Aß)-directed active and passive immunization therapeutic strategies reduce brain levels of Aß, decrease the severity of beta-amyloid plaque pathology and reverse cognitive deficits in mouse models of Alzheimer's disease (AD). As an alternative approach to passive immunization with full IgG molecules, single-chain variable fragment (scFv) antibodies can modulate or neutralize Aß-related neurotoxicity and inhibit its aggregation in vitro. In this study, we characterized a scFv derived from a full IgG antibody raised against the C-terminus of Aß, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aß-related pathology. We found that the scFv entered the brain after intranasal application, and that it bound to beta-amyloid plaques in the cortex and hippocampus of APP transgenic mice. Moreover, the scFv inhibited Aß fibril formation and Aß-mediated neurotoxicity in vitro. In a preventative therapeutic approach chronic intranasal treatment with scFv reduced congophilic amyloid angiopathy (CAA) and beta-amyloid plaque numbers in the cortex of APPswe/PS1dE9 mice. This reduction of CAA and plaque pathology was associated with a redistribution of brain Aß from the insoluble fraction to the soluble peptide pool. Due to their lack of the effector domain of full IgG, scFv may represent an alternative tool for the treatment of Aß-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aß-directed immunotherapy can reduce Aß deposition in brain vessels in transgenic mice.