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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 Aβ_{1-42} on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20–200 nM) of Aβ_{1-42} 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 Aβ_{1-42}, which occurred at 20 nM of Aβ, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Aβ_{1-42} 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. [ABSTRACT FROM AUTHOR]

As an important molecule in the pathogenesis of Alzheimer's disease (AD), amyloid-β (Aβ) interferes with multiple aspects of mitochondrial function, including energy metabolism failure, production of reactive oxygen species (ROS) and permeability transition pore formation. Recent studies have demonstrated that Aβ progressively accumulates within mitochondrial matrix, providing a direct link to mitochondrial toxicity. Aβ-binding alcohol dehydrogenase (ABAD) is localized to the mitochondrial matrix and binds to mitochondrial Aβ. Interaction of ABAD with Aβ exaggerates Aβ-mediated mitochondrial and neuronal perturbation, leading to impaired synaptic function, and dysfunctional spatial learning/memory. Thus, blockade of ABAD/Aβ interaction may be a potential therapeutic strategy for AD. [ABSTRACT FROM AUTHOR]