Hormetic effect of amyloid-beta peptide in synaptic plasticity and memory.

Background: The term hormesis refers to a biphasic dose-response phe- nomenon characterized by low-dose stimulation and high-dose inhibi- tion (represented for instance by an inverted-U-shaped curve) that might be due to a disruption in homeostasis after exposure to low levels of a toxic substance (Calabrese, Br J Clin Pharmacol, 2008). It is well known that high levels of amyloid-ß peptide (Aß) are present during Alzheimer’s disease, causing synaptic and memory dysfunction (Selkoe, Science, 2002; Cleary et al, Nat Neurosci, 2005) whereas low picomo- lar concentrations of a preparation containing both Aß42 monomers and oligomers cause a marked increase of hippocampal long-term potentia- tion and reference and contextual fear memory (Puzzo et al, J Neurosci, 2009), suggesting a potential therapeutical role of low concentration of the peptide for memory dysfunction. Methods: We studied concentra- tion-response curves to test whether Aß has a hormetic effect on hippo- campal-dependent memory, tested by Fear Conditioning and Morris Water-Maze test on mice. We also investigated the effect of “very low doses” of a mixed preparation of Aß42 on synaptic transmission (post-te- tanic potentiation and long-term potentiation) and hippocampal-depen- dent memory. Results: We found that Aß has a hormetic effect on hippocampal-dependent memory. Moreover, “very low doses” of the pep- tide are able to enhance synaptic plasticity and memory depending on the dose and time of application. Conclusions: Hormesis theory might be use- ful to understand the “biphasic” effect of; Aß on synaptic plasticity and memory. Paradoxically, Aß itself might serve to enhance memory at appro- priate concentrations and conditions.