Aβ oligomer elimination decreases tau oligomer concentration in CSF and enhances cognition in cognitively impaired aged Beagle dogs ‐ a model of sporadic Alzheimer’s disease

Abstract

AbstractBackgroundDisease‐modifying therapies to treat Alzheimer’s disease (AD) are of fundamental interest for aging humans, societies, and health care systems. More and more data suggest that the toxic protein assemblies of Aβ and tau behave prion like. The drug candidate RD2 (alias PRI‐002) has been developed to directly disassemble and disrupt toxic Aβ oligomer prions. The anti‐prionic compound is BBB penetrable and has demonstrated target engagement in vitro, ex vivo and in vivo. Treatment with RD2 has yielded improved cognition and deceleration of neurodegeneration in three different transgenic mouse models in three different laboratories. Cognitively impaired aged Beagle dogs are one of the very few non‐transgenic AD animal models that may simulate the situation of spontaneous late onset AD, i.e. sporadic AD, which is the most common form of AD in humans. The aim of this study was to investigate the efficacy of RD2 to enhance short‐term memory and cognition in cognitively impaired aged Beagle dogs ‐ a non‐transgenic model of sporadic AD.Method36 cognitively impaired aged Beagle dogs have been randomized for five months in three cohorts, placebo, low dose (3 mg/kg RD2 once daily) and high dose (30 mg/kg RD2 once daily). Treatment was done orally and for three months, followed by two months without treatment. Cognitive testing, blood and CSF drawing was done at baseline and then monthly.ResultWe demonstrate that once daily oral treatment with RD2 significantly reduced cognitive deficits in cognitively impaired aged Beagle dogs even beyond the end of the treatment. This and treatment dependent CSF tau oligomer decrease clearly suggest a neuroprotective and truly disease‐modifying effect of RD2 treatment.ConclusionDirect elimination of Aβ oligomers by disassembling them into monomers is an interesting therapeutic strategy for AD disease modification including beneficial symptomatic effects.