期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 2, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s40478-014-0175-x
关键词
Alzheimer's disease; Amyloid beta; Transgenic rat; Long-term potentiation (LTP); Secretase inhibitor; Immunotherapy; Longitudinal
资金
- Centres of Excellence in Neurodegeneration (CoEN) initiative
- Science Foundation Ireland
- Health Research Board of Ireland
- National Institutes of Health [R01-NS33249]
- German Research foundation [CRC1089]
- Canadian Institutes of Health Research [MOP 102752]
- Merck Canada
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS033249] Funding Source: NIH RePORTER
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 A beta 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 A beta antibody, McSA1, transiently reversed the impairment of synaptic plasticity. Similar brief treatment with the BACE1 inhibitor LY2886721 or the.-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 A beta 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.
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