Background: Abnormally high levels of amyloid-b peptide (Ab) are likely to play a major role in Alzheimer’s Disease (AD) (Selkoe, Science, 2002; Cleary et al, Nat Neurosci, 2005). However, Ab is normally produced in the brain, where it is regulated by synaptic activity, primarily through vesicle exocytosis (Cirrito et al, Neuron, 2005) and reaches a concentration that in rodents has been estimated to be in the picomolar range (Schmidt et al, Methods Mol Biol, 2005). Despite its presence throughout life in normal in- dividuals, it is not clear whether Ab has a physiological role in the brain. In a previous paper (Puzzo et al, J Neurosci, 2008) we demonstrated that pico- molar concentration of synthetic Ab enhances synaptic plasticity and mem- ory via a7-nAchRs. Methods: Here, we investigated the role of endogenous Ab in the regulation of short- and long-term synaptic plasticity including long-term potentiation, post-tetanic potentiation and paired pulse facilitation, as well as in two different forms of hippocampal-dependent memory, includ- ing contextual fear learning and spatial memory, tested with the Morris water- maze. We acutely depleted endogenous Ab using a specific anti-rodent Ab monoclonal antibody (JRF/rAb2), as well as siRNA against rodent APP, prior to eliciting synaptic plasticity and memory. Moreover, we performed rescue ex- periments with a mixed preparation containing both oligomeric and monomeric human Ab42 (Stine et al, J Biol Chem, 2003), to assess if the effects of the an- tibody and APP-siRNA on synaptic plasticity and memory were specifically due to murine Ab42. Results: We found that depletion of endogenously pro- duced Ab42 reduced synaptic plasticity and memory. These impairments were rescued by the human Ab42 preparation, but not the monomeric species alone. In addition, they involved regulation of transmitter release occurring at the time of their induction, and a7-containing nicotinic acetylcholine receptors. Conclusions: Endogenous oligomeric Ab42 is needed for induction of synap- tic plasticity and memory acquisition within the normal CNS.
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