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OBJECTIVE: The goal of this study was to investigate the role of endogenous amyloid-β peptide (Aβ) 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 Aβ 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 Aβ₄₂, suggesting that endogenously produced Aβ is needed for normal LTP and memory. Furthermore, the effect of endogenous Aβ on plasticity and memory was likely due to regulation of transmitter release, activation of α7-containing nicotinic acetylcholine receptors, and Aβ₄₂ production. INTERPRETATION: Endogenous Aβ₄₂ 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 Aβ levels to treat Alzheimer disease.

Original publication

DOI

10.1002/ana.22313

Type

Journal article

Journal

Ann Neurol

Publication Date

05/2011

Volume

69

Pages

819 - 830

Keywords

Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Antibodies, Behavior, Animal, Biophysics, Electric Stimulation, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Hippocampus, Humans, Long-Term Potentiation, Male, Maze Learning, Memory, Mice, Mice, Inbred C57BL, Peptide Fragments, RNA, Small Interfering