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 (PrPC) initiates synaptic damage as a high affinity receptor for Aßo. Here, we evaluated the preclinical therapeutic efficacy of a fully human monoclonal antibody against PrPC. This AZ59 antibody selectively targets the Aβo binding site in the amino‐terminal unstructured domain of PrPC to avoid any potential risk of direct toxicity. Methods Potency of AZ59 was evaluated by binding to PrPC, 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 PrPC with 100 pmol/L affinity and blocks human brain Aßo binding to PrPC, 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.

Soluble Prion Peptide 107–120 Protects Neuroblastoma SH-SY5Y Cells against Oligomers Associated with Alzheimer’s Disease

“…One year later, Chen and co-workers showed that both N -terminal residues 23–27 and 92–110 were critically important for binding [ 36 ]. The importance of these two sequence regions was then confirmed by later reports [ 13 , 14 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

“…Previous studies have suggested that the cell surface protein PrP C mediates the toxicity of Aβ 42 oligomers by binding to them and affecting synaptic plasticity and other neuronal functions [ 13 , 14 , 15 , 16 , 17 , 18 ], although a general consensus on this point has not yet been found [ 19 , 20 , 21 ]. One PrP C region of the sequence thought to be involved in Aβ 42 binding encompasses approximately residues 95–110 [ 13 , 14 , 33 , 34 , 35 , 37 , 38 , 39 , 40 , 41 , 42 ]. An antibody raised against residues 93–109 of PrP C (anti-PrP C 93–109 GD11) and a synthetic peptide corresponding to residues 98–107 (PrP 98–107 ) were found to inhibit the toxicity of the Aβ 42 ADDLs to organotypic hippocampal slices, whereas a control PrP 213–230 peptide did not have any such effects [ 37 ].…”

Cellular Prion Protein as a Receptor of Toxic Amyloid-β42 Oligomers Is Important for Alzheimer’s Disease

“…Pretreatment with an antibody against residues 93–109 of PrP C , 6D11, can prevent neuronal cell death by oligomeric Aβ42 and rescues cognitive deficits in APP/PS1 transgenic mice, while another antibody against residues 144–152 of PrP C , 6H4, fails to block oligomeric Aβ-induced neuronal toxicity (Chung et al, 2010; Kudo et al, 2012). Recently, another antibody against resides 23–111 of PrP C was reported to rescue synapses and cognitive deficits in APP/PS1 mice (Cox et al, 2019).…”

Advancing medicine for Alzheimer’s disease: A plasma neural exosome platform

“…This regimen of intact anti-PrPc antibody treatment normalized both the behavioral disturbances and synaptic losses of AD mice relative to control mice for up to 1 month after the last dose. 28 This dramatic outcome requires validation in other types of AD mice with Fab as well as intact antibody, and with additional anti-PrPc antibody controls.…”

“…Such therapy will reduce and delay the synaptic dysfunction and cerebral microvascular diseases attributable to binding of these neuropathogenic proteins to their neuronal and endothelial receptors, as already suggested by a few early studies in animal models. 28,44 It is expected that therapies directed to the later amplification processes may include complement C3 convertase inhibitors, neuronal survival factors such as leukemia inhibitory factor (LIF) and SOD mimetics. Although these agents may be beneficial even late in the course of AD, their effects are unlikely to be as striking as those of antibodies and drugs preventing initial actions of primary neuropathic proteins on neurons.…”