Oral Treatment with a gamma-Secretase Inhibitor Improves Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

The beta-amyloid peptide (A beta) is thought to play a critical role in the pathophysiology of Alzheimer's disease (AD). To study the effects of A beta on the brain, transgenic mouse models have been developed that express high levels of A beta. These mice show some features of AD, including amyloid plaques and mild cognitive impairment, but not others such as progressive neurodegeneration. We investigated the age-dependent effects of A beta on synaptic physiology in Tg2576 mice that express human A beta. We report that both basal synaptic activity and long-term potentiation (LTP), as measured in the CA1 region of the hippocampus, were compromised by 7 months of age before plaque deposition. Despite a persistent increase in A beta levels with age, LTP recovered in 14-month-old mice, with no further loss of basal activity compared with activity measured in 7-month-old mice. Previous work has shown that inhibitors of gamma-secretase, an enzyme critical for A beta synthesis, can significantly reduce A beta production and plaque formation in Tg2576 mice. Our data demonstrate that 7-month-old Tg2576 mice treated with an orally available gamma-secretase inhibitor showed a significant improvement in synaptic function and plasticity within days, and the effect was correlated with the extent and duration of A beta reduction. These results indicate that recovery from A beta-mediated synaptotoxicity can occur rapidly with A beta lowering therapies. These findings highlight some of the strengths and limitations of using A beta-overexpressing mouse models for Alzheimer's drug discovery.