Preventing Alzheimer's Pathology in a Preclinical Mouse Model

Abstract

More than five million people live with Alzheimer's disease (AD) in the U.S. today and the number is rapidly rising. This disease robs its victims of dignity and places untold burden on families and on the economy. Cystatin C (CysC) is highly expressed in normal brain, but drops at the onset of AD and remains low during AD progression. Forced expression of CysC lowers Aβ brain deposition in AD mouse models. Since CysC protein can both inhibit amyloid precursor protein (APP) degradation by cathepsin B and prevent Aβ fibril formation in vitro, we synthesized the Aβ‐binding portion (CysC‐AβBP), labeled it with FITC and showed that it binds specifically to Aβ42 oligomers, that it can be efficiently delivered to the brain intranasally and that, when intranasally delivered into an AD mouse model, it binds to Aβ in the hippocampus and the neocortex. In our in vivo studies, 2.7 and 4 month old CRND8 AD mouse littermates were treated intranasally with 20 micrograms of CysC‐AβBP or scrambled CysC‐AβBP peptide, twice weekly for 3 weeks. Sagittal sections of brains from untreated and treated AD mice were stained with Aβ‐specific antibody 6E10 (Covance) and Texas Red‐conjugated secondary antibody. 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. Importantly, a 3‐week treatment of AD mice with CysC‐AβBP reduces Aβ aggregates and plaque up to 80% in the hippocampus and neocortex.