Alzheimer's Disease Brain-Derived Amyloid-β-Mediated Inhibition of LTP<i>In Vivo</i>Is Prevented by Immunotargeting Cellular Prion Protein

Abstract

Synthetic amyloid-β protein (Aβ) oligomers bind with high affinity to cellular prion protein (PrP C ), but the role of this interaction in mediating the disruption of synaptic plasticity by such soluble Aβ in vitro is controversial. Here we report that intracerebroventricular injection of Aβ-containing aqueous extracts of Alzheimer's disease (AD) brain robustly inhibits long-term potentiation (LTP) without significantly affecting baseline excitatory synaptic transmission in the rat hippocampus in vivo . Moreover, the disruption of LTP was abrogated by immunodepletion of Aβ. Importantly, intracerebroventricular administration of antigen-binding antibody fragment D13, directed to a putative Aβ-binding site on PrP C , prevented the inhibition of LTP by AD brain-derived Aβ. In contrast, R1, a Fab directed to the C terminus of PrP C , a region not implicated in binding of Aβ, did not significantly affect the Aβ-mediated inhibition of LTP. These data support the pathophysiological significance of SDS-stable Aβ dimer and the role of PrP C in mediating synaptic plasticity disruption by soluble Aβ.

Keywords

Affiliated Institutions

• University College Dublin IE
• Beaumont Hospital IE
• Trinity College Dublin IE

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