ß-AMYLOID-OLIGOMER-INDUCED ALZHEIMER’S MODEL SHOWS SYNAPTIC DEGRADATION FOR USE IN TARGET VALIDATION AND DRUG DEVELOPMENT

Abstract

Oligomeric forms of β-amyloid peptide (AβO) are widely accepted as the initial cause for neurodegeneration in Alzheimer’s disease (AD), related mild-cognitive impairment (MCI) and dementia, also triggering neuro-inflammatory processes and other complications. To reduce the significant attrition during drug discovery for neurodegenerative diseases, translational in vitro and in vivo models are essential. Here, we report highly reproducible in vitro and in vivo AD models, based on the neurodegenerative effects of a single injection of AβO preparations. Our AβO preparations induce dramatic neuronal cell death (monitored using multiple read-outs) in rodent primary neurons from different brain areas, as well as in human neurons derived from iPS cells. AβO-induced neuronal apoptosis is associated with neuro-inflammatory processes, increased production of pro-inflammatory cytokines, and impairment of sphingolipid cell signaling. In rodent models (mice and rats), a single brain injection of minute amounts of AβO results in dramatic and fast impairment of cognitive functions, associated with synaptic dysfunctions. A remarkable loss of synaptic marker proteins has indeed been found. Unlike transgenic models, our acute models imitate sporadic AD, are easily scalable to statistically meaningful animal numbers, and are successfully used for fast and cost effective phenotypic validation of preclinical candidates.