Chronic Intranasal Treatment with an Anti-A[beta].sub.30-42 scFv Antibody Ameliorates Amyloid Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Amyloid-beta peptide (A[beta])-directed active and passive immunization therapeutic strategies reduce brain levels of A[beta], 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 A[beta]-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 A[beta], and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce A[beta]-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 A[beta] fibril formation and A[beta]-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 A[beta] 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 A[beta]-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that A[beta]-directed immunotherapy can reduce A[beta] deposition in brain vessels in transgenic mice.