Long before synaptic loss occurs in Alzheimer's disease significant harbingers of disease may be detected at the functional level. Here we examined if synaptic long-term potentiation is selectively disrupted prior to extracellular deposition of Aß in a very complete model of Alzheimer's disease amyloidosis, the McGill-R-Thy1-APP transgenic rat. Longitudinal studies in freely behaving animals revealed an age-dependent, relatively rapid-onset and persistent inhibition of long-term potentiation without a change in baseline synaptic transmission in the CA1 area of the hippocampus. Thus the ability of a standard 200 Hz conditioning protocol to induce significant NMDA receptor-dependent short- and long-term potentiation was lost at about 3.5 months of age and this deficit persisted for at least another 2-3 months, when plaques start to appear. Consistent with in vitro evidence for a causal role of a selective reduction in NMDA receptor-mediated synaptic currents, the deficit in synaptic plasticity in vivo was associated with a reduction in the synaptic burst response to the conditioning stimulation and was overcome using stronger 400 Hz stimulation. Moreover, intracerebroventricular treatment for 3 days with an N-terminally directed monoclonal anti- human Aß antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the γ-secretase inhibitor MRK-560 was found to have a comparable short-lived ameliorative effect when tracked in individual rats. These findings provide strong evidence that endogenously generated human Aß selectively disrupts the induction of long-term potentiation in a manner that enables potential therapeutic options to be assessed longitudinally at the pre-plaque stage of Alzheimer's disease amyloidosis.
|Original language||English (US)|
|Journal||Acta Neuropathologica Communications|
|State||Published - Jan 27 2014|
Bibliographical noteFunding Information:
Acknowledgments We thank Prof Roger Anwyl for his help and encouragement. This work was supported by grants from Centres of Excellence in Neurodegeneration (CoEN) initiative (ACC, MF, SR and MJR), Science Foundation Ireland (MJR), the Health Research Board of Ireland (IK, MJR), the National Institutes of Health (R01-NS33249: KHA, MKG), the German Research foundation CRC1089 (MF, SR), Canadian Institutes of Health Research (MOP 102752: ACC). We are thankful to have the support of Alan Frosst and the Frosst family (ACC) and Merck Canada.
© 2014 Qi et al.; licensee BioMed Central.
- Alzheimer's disease
- Amyloid ß
- Long-term potentiation (LTP)
- Secretase inhibitor
- Transgenic rat