Search

Oligomeric amyloid-beta (Abeta) interferes with long-term potentiation (LTP) and cognitive processes, suggesting that Abeta 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 Abeta-induced neuronal and synaptic dysfunction. In the present study, we investigated the effect of oligomeric soluble Abeta1-42 on LTP elicited by the stimulation of different intracortical pathways in the mouse visual cortex. A variety of nanomolar concentrations (20-200 nM) of Abeta1-42 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 Abeta1-42, which occurred at 20 nM of Abeta, when stimulating layer II-III horizontal pathway. Remarkably, cortical slices were resistant to nanomolar Abeta1-42 in the absence of RAGE (genetic deletion of RAGE) or blocking RAGE by RAGE antibody. These results indicate that nanomolar Abeta inhibits LTP expression in different neocortical circuits. Crucially, it is demonstrated that Abeta-induced reduction of LTP in different cortical pathways is mediated by RAGE. [ABSTRACT FROM AUTHOR]

In the past thirty years, nerve growth factor (NGF) has received much attention for its potential role as a therapeutic agent for Alzheimer's disease (AD) due to its neurotrophic activities on basal forebrain cholinergic neurons. This attention has been renewed by recent findings that provide new causal links between defects in NGF signaling, transport or processing to the activation of the amyloidogenic route and, more generally, to AD neurodegeneration. Thus, the concept of therapeutic administration of human recombinant NGF in AD patients has a strong rationale, being further validated by recent and ongoing clinical trials with a gene-therapy approach. However, the widespread clinical application of gene or cell-therapy strategies for the delivery of NGF to AD patients seems unpractical, and it would be more advantageous to have non-invasive methods, that should also limit the adverse effects of NGF in activating nociceptive responses. This review will describe: 1) the data from preclinical and clinical studies underlying the rationale of NGF as a potential therapeutic agent for AD; and 2) the alternative strategies to reach adequate concentrations of NGF in relevant brain areas while preventing the onset of adverse effects. [ABSTRACT FROM AUTHOR]