Abstract
Amyloid-beta peptide (Aβ)-directed active and passive immunization therapeutic strategies reduce brain levels of Aβ, 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 Aβ-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 Aβ, and studied its passage into the brains of APP transgenic mice, as well as its potential to reduce Aβ-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 Aβ fibril formation and Aβ-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 Aβ 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 Aβ-related pathology without triggering Fc-mediated effector functions. Additionally, our observations support the possibility that Aβ-directed immunotherapy can reduce Aβ deposition in brain vessels in transgenic mice.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia in the aged population and the number of patients is continuously increasing due to a lack of effective treatments
Generation of the amyloid b- peptide (Ab) from the amyloid precursor protein (APP) by b- and c-cleavage followed by seeded aggregation of Ab is widely believed to be the initiating event in the pathogenesis of AD [3] resulting in sustained deposition of Ab in brain parenchyma and cerebral blood vessels [4]
Humanisation of scFv was performed by grafting the complementarity determining regions (CDRs) of the variable domain (VL) and VH domains into a human scFv framework leading to the single chain antibody 22C4 scFv
Summary
Alzheimer’s disease (AD) is the most common form of dementia in the aged population and the number of patients is continuously increasing due to a lack of effective treatments. The histopathological characteristics are extracellular amyloid deposits and intracellular neurofibrillary tangles. The accumulation of these protein aggregates is accompanied by synaptic dysfunction, inflammation and eventually neuronal death [2]. Generation of the amyloid b- peptide (Ab) from the amyloid precursor protein (APP) by b- and c-cleavage followed by seeded aggregation of Ab is widely believed to be the initiating event in the pathogenesis of AD [3] resulting in sustained deposition of Ab in brain parenchyma and cerebral blood vessels [4]. Because Ab aggregates are neurotoxic, numerous strategies to prevent Ab aggregation and accumulation are currently studied as potential ways to treat or prevent AD
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