Affiliations: [a] Institute of Neuroscience (CNR), Pisa, Italy | [b] European Brain Research Institute, Roma, Italy | [c] International School for Advanced Studies (SISSA), Trieste, Italy | [d] Department of Pathology and Surgery & Taub Institute, Columbia University, New York, USA | [e] Department STB, University of L'Aquila, L'Aquila, Italy
Correspondence:
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Corresponding author: Luciano Domenici, Institute of Neuroscience (C.N.R.), Via G. Moruzzi 1, 56100, Pisa, Italy. Tel.: +39 50 3153182; Fax: +39 50 3153220; E-mail: [email protected].
Abstract: Oligomeric amyloid-β (Aβ) interferes with long term potentiation (LTP) and cognitive processes, suggesting that Aβ peptides may play a role in the neuronal dysfunction which characterizes the early stages of Alzheimer's disease (AD). Multiple lines of evidence have highlighted RAGE (receptor for advanced glycation end-products) as a receptor involved in Aβ-induced neuronal and synaptic dysfunction. In the present study, we investigated the effect of oligomeric soluble Aβ1-42 on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20–200 nM) of Aβ1-42 were able to inhibit LTP in cortical layer II-III induced by either white matter (WM-Layer II/III) or the layer II/III (horizontal pathway) stimulation, whereas the inhibition of LTP was more susceptible to Aβ1-42, which occurred at 20 nM of Aβ, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Aβ1-42 in the absence of RAGE (genetic deletion of RAGE) or blocking RAGE by RAGE antibody. These results indicate that nanomolar Aβ inhibits LTP expression in different neocortical circuits. Crucially, it is demonstrated that Aβ-induced reduction of LTP in different cortical pathways is mediated by RAGE.
