Inhibitory effect of amyloid-β peptide with the Arctic mutation on long-term potentiation in area CA1 of rat hippocampus in vivo

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  • Inhibitory effect of amyloid-β peptide with the Arctic mutation on long-term potentiation in area CA1 of rat hippocampus in vivo

Trinity College, Dublin (2003) J Physiol 551P, C32

Communications: Inhibitory effect of amyloid-β peptide with the Arctic mutation on long-term potentiation in area CA1 of rat hippocampus in vivo

I. Klyubin*, D.M. Walsh†, R. Anwyl‡, D.J. Selkoe† and M.J. Rowan*

* Department of Pharmacology and Therapeutics and ‡Department of Physiology, Trinity College Dublin, Ireland and †Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA

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The Arctic (E22G) point mutation within the hydrophobic core of amyloid β (Aβ) peptide sequence is associated with a familial form of Alzheimer’s disease. The G22 mutation appears to change aggregation of the peptide in the absence of an increase in total Aβ secretion. Previously, we showed that oligomers are the species responsible for the block of long-term potentiation (LTP) by Aβ (Walsh et al. 2002). Here we compared the effects of I.C.V. injection of wild-type (WT) and E22G Aβ1-40 peptides on LTP in the CA1 area of urethane (1.5 g kg-1 I.P.)-anaesthetised male adult Wistar rats.

The animal care and experimental protocol including humane killing were licensed by the Department of Health, Republic of Ireland. Statistical comparisons were made by Student’s paired t test. Values are expressed as the mean percentage of the baseline field EPSP amplitude ± S.E.M.

In control, vehicle-injected animals, 200 Hz high frequency stimulation (HFS) induced a robust and stable LTP (148 ± 6 % at 3 h post HFS, P < 0.0001, n = 6). Aβ WT (5 µl of a 100 µM solution) only partially blocked LTP (122 ± 4 %, P < 0.001, n = 5) and did not affect baseline synaptic transmission (103 ± 5 % at 3 h post injection, P > 0.7, n = 4). In contrast, E22G Aβ at a concentration as low as 0.9 µM completely blocked LTP (99 ± 5 %, P > 0.2, n = 4). Although this concentration of E22G Aβ did not affect baseline transmission (101 ± 4 %, P > 0.1, n = 4), a higher concentration (42 µM) reduced the baseline EPSP amplitude (62 ± 7 %, P < 0.005, n = 4). In order to determine if the different activity of the peptides was due to differences in assembly state we performed biophysical characterization of the peptides in solution. The Congo Red assay and electron microscopy showed that while both WT and mutant Aβ formed aggregates, the E22G solution contained larger structures. To compare the relative activities of the peptide in a defined assembly state we removed large aggregates (fibrils) by ultracentrifugation. Injection of this E22G solution (1 µM) also blocked LTP (99 ± 5 %, P > 0.4, n = 6).

These data suggest that the functional differences between the WT and E22G Aβ peptides may be the result of increased formation of soluble assemblies by the Arctic mutation.

This work was supported by Science Foundation Ireland and the Irish Research Council for Science, Engineering and Technology (M.J.R. and R.A.) and NIH grant (D.J.S.).

Where applicable, experiments conform with Society ethical requirements.

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