Aim: 

Abnormally high levels of amyloid-b peptide (Ab) are likely to play a major role in Alzheimer's Disease (AD). However, A? is normally produced in the brain, where it is regulated by synaptic activity, primarily through vesicle exocytosis and reaches a concentration that in rodents has been estimated to be in the picomolar range. Despite its presence throughout life in normal individuals, it is not clear whether A? has a physiological role in the brain. In a previous paper (Puzzo et al, J Neurosci, 2008) we demonstrated that picomolar concentration of synthetic A? enhances synaptic plasticity and memory via a7-nAchRs. Here, we investigated whether A? is necessary for synaptic plasticity and memory.

Methods: 

We investigated the role of endogenous A? 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, including contextual fear learning and spatial memory, tested with the Morris water-maze. We acutely depleted endogenous A? using a specific anti-rodent A? monoclonal antibody (JRF/rAb2), as well as siRNA against rodent APP, prior to eliciting synaptic plasticity and memory. Moreover, we performed rescue experiments with a mixed preparation containing both oligomeric and monomeric human A?42, to assess if the effects of the antibody and APP-siRNA on synaptic plasticity and memory were specifically due to murine Ab42.

Results: 

We found that depletion of endogenously produced A? reduced synaptic plasticity and memory. These impairments were rescued by the human? A? 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.

Conclusion: 

Endogenous oligomeric A?42 is needed for induction of synaptic plasticity and memory acquisition within the normal CNS.