Anti‐PrP ^C antibody rescues cognition and synapses in transgenic alzheimer mice

Abstract

Objective

Amyloid‐beta oligomers (Aßo) trigger the development of Alzheimer's disease ( AD) pathophysiology. Cellular prion protein (Pr PC) initiates synaptic damage as a high affinity receptor for Aßo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against Pr PC. This AZ59 antibody selectively targets the Aβo binding site in the amino‐terminal unstructured domain of Pr PC to avoid any potential risk of direct toxicity.

Methods

Potency of AZ59 was evaluated by binding to Pr PC, blockade of Aβo interaction and interruption of Aβo signaling. AZ59 was administered to mice by weekly intraperitoneal dosing and brain antibody measured. APP/ PS1 transgenic mice were treated with AZ59 and assessed by memory tests, by brain biochemistry and by histochemistry for Aß, gliosis and synaptic density.

Results

AZ59 binds Pr PC with 100 pmol/L affinity and blocks human brain Aßo binding to Pr PC, as well as prevents synaptotoxic signaling. Weekly i.p. dosing of 20 mg/kg AZ59 in a murine form achieves trough brain antibody levels greater than 10 nmol/L. Aged symptomatic APP/ PS1 transgenic mice treated with AZ59 for 5–7 weeks show a full rescue of behavioral and synaptic loss phenotypes. This recovery occurs without clearance of plaque pathology or elimination of gliosis. AZ59 treatment also normalizes synaptic signaling abnormalities in transgenic brain. These benefits are dose‐dependent and persist for at least 1 month after the last dose.

Interpretation

Preclinical data demonstrate that systemic AZ59 therapy rescues central synapses and memory function from transgenic Alzheimer's disease pathology, supporting a disease‐modifying therapeutic potential.