Intranasal Delivery of a Cystatin C‐peptide as Therapy for Alzheimer's Disease

Abstract

Our long‐term goal is to develop therapies for Alzheimer's disease based on CysC‐AβBP, a peptide known to bind amyloid beta peptides and prevent their oligmerization in vitro. We hypothesize that this intervention should reduce amyloid beta diffusible ligands and plaque deposition, as well as improve memory in AD mice. Our results indicate that CysC‐AβBP binds specifically and preferentially to purified Aβ42 (a scrambled peptide does not bind Aβ42), and that in 2 AD mouse models, one with amyloid plaques and oligomers (oAβ) (TgCRND8) and one with oAβ only (APPE693Q), CysC‐AβBP co‐localizes with Aβ deposits in the neocortex and hippocampus when incubated with brain sections in vitro. In our in vivo studies, 2.7 and 4 month old CRND8 AD mouse littermates were treated intranasally with 20 μg of CysC‐AβBP or scrambled AβBP peptide, twice weekly for 3 weeks. The brain sections from untreated and treated AD were treated with amyloid beta specific antibody 6E10. The brains of AD mice with no treatment or scrambled peptide treatment had a large accumulation of amyloid beta aggregates and plaque in the neocortex and hippocampus. In contrast, we observed a profound reduction in β‐amyloid aggregates and plaques in the neocortex and hippocampus of CysC‐AβBP treated AD mice. Our results suggest that CysC‐AβBP reduces amyloid aggregates and plaque in animals developing AD and in animals with established AD.