LPYFDa Neutralizes Amyloid-β-Induced Memory Impairment and Toxicity

Abstract

Misfolding, oligomerization, and aggregation of the amyloid-β (Aβ) peptide is widely recognized as a central event in the pathogenesis of Alzheimer's disease (AD). Recent studies have identified soluble Aβ oligomers as the main pathogenic agents and provided evidence that such oligomeric Aβ aggregates are neurotoxic, disrupt synaptic plasticity, and inhibit long-term potentiation. A promising therapeutic strategy in the battle against AD is the application of short synthetic peptides which are designed to bind to specific Aβ-regions thereby neutralizing or interfering with the devastating properties of oligomeric Aβ species. In the present study, we investigated the neuroprotective properties of the amyloid sequence derived pentapeptide LPYFDa in vitro as well as its memory preserving capacity against Aβ₄₂-induced learning deficits in vivo. In vitro we showed that neurons in culture treated with LPYFDa are protected against Aβ₄₂-induced cell death. Moreover, in vivo LPYFDa prevented memory impairment tested in a contextual fear conditioning paradigm in mice after bilateral intrahippocampal Aβ₄₂ injections. We thus showed for the first time that an anti-amyloid peptide like LPYFDa can preserve memory by reverting Aβ₄₂ oligomer-induced learning deficits.