Endogenous amyloid-β is necessary for hippocampal synaptic plasticity and memory.

Objective: The goal of this study was to investigate the role of endogenous amyloid-beta peptide (A beta) in healthy brain. Methods: Long-term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduced through small interfering RNA (siRNA) technique. Results: We found that both antirodent A beta antibody and siRNA against murine APP reduced LTP as well as contextual fear memory and reference memory. These effects were rescued by the addition of human A beta(42), suggesting that endogenously produced A beta is needed for normal LTP and memory. Furthermore, the effect of endogenous A beta on plasticity and memory was likely due to regulation of transmitter release, activation of alpha 7-containing nicotinic acetylcholine receptors, and A beta(42) production. Interpretation: Endogenous A beta(42) is a critical player in synaptic plasticity and memory within the normal central nervous system. This needs to be taken into consideration when designing therapies aiming at reducing A beta levels to treat Alzheimer disease. ANN NEUROL 2011; 69: 819-830