Hormetic effect of amyloid-beta peptide in hippocampal synaptic plasticity and memory
Keywords:hormesis, peptide, hippocampal
AbstractBackground: The term hormesis refers to a biphasic dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition represented by a J-shaped or U-shaped curve, depending on the parameter measured (Calabrese and Baldwin, Hum Exp Toxicol, 2002). Indeed, several, if not all, physiological molecules (i.e. glutamate, glucocorticoids, nitric oxide) are likely to present a hormetic effect, exhibiting opposite effects at high or low concentrations. In the last few years, we have focused on amyloid-beta (AÃƒÂ¯Ã‚ÂÃ‚Â¢), a peptide widely known because it is produced in high amounts during AlzheimerÃƒÂ¢Ã¢â€šÂ¬Ã¢â€žÂ¢s disease (AD). AÃƒÂ¯Ã‚ÂÃ‚Â¢ is considered a toxic fragment causing synaptic dysfunction and memory impairment (Selkoe, Science, 2002). However, the peptide is normally produced in the healthy brain and growing evidences indicate that it might have a physiologic function. Aim: Based on previous results showing that picomolar concentrations of AÃƒÂ¯Ã‚ÂÃ‚Â¢42 enhance synaptic plasticity and memory (Puzzo et al, J Neurosci, 2008) and that endogenous AÃƒÂ¯Ã‚ÂÃ‚Â¢ is necessary for synaptic plasticity and memory (Puzzo et al, Ann Neurol, 2011), the aim of our study was to demonstrate the hormetic role of AÃƒÂ¯Ã‚ÂÃ‚Â¢ in synaptic plasticity and memory. Methods: We used 3-month old wild type mice to analyze how synaptic plasticity, measured on hippocampal slices in vitro, and spatial reference memory were modified by treatment with different doses of AÃƒÂ¯Ã‚ÂÃ‚Â¢ (from 2 pM to 20 ÃƒÅ½Ã‚Â¼M). Results: We demonstrated that AÃƒÂ¯Ã‚ÂÃ‚Â¢ has a hormetic effect (Puzzo et al, Neurobiol Aging, 2012) with low-doses (200 pM) stimulating synaptic plasticity and memory and high-doses (ÃƒÂ¢Ã¢â‚¬Â°Ã‚Â¥ 200 nM) inhibiting these processes. Conclusions: Our results suggest that, paradoxically, very low doses of AÃƒÂ¯Ã‚ÂÃ‚Â¢ might serve to enhance memory at appropriate concentrations and conditions. These findings raise several issues when designing effective and safe approaches to AD therapy.
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