Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo

The effect of intracerebroventricular (icv) injections of beta -amyloid pep tide fragments A beta [15-25], A beta [25-35], and A beta [35-25] were exam ined on synaptic transmission and long-term potentiation (LTP) in the hippo campal CA1 region in vivo. Rats were anesthetized using urethan, and change s in synaptic efficacy were determined from the slope of the excitatory pos tsynaptic potential (EPSP). Baseline synaptic responses were monitored for 30 min prior to icv injection of A beta peptides or vehicle. High-frequency stimulation (HFS) to induce LTP was applied to the Schaffer-collateral pat hway 5 min or 1 h following the icv injection. HFS comprised 3 episodes of 10 stimuli at 200 Hz, 10 times, applied at 30-s intervals. Normal LTP measu red 30 min following HFS, was produced following icv injection of vehicle ( 191 +/- 17%, mean +/- SE, n = 6) or A beta [15-25; 100 nmol] (177 +/- 6%, n 5 6) 1 h prior to HFS. LTP was, however, markedly reduced by A beta [25-35 ; 10 nmol] (129 +/- 9%, n = 6, P < 0.001) and blocked by A<beta>[25-35; 100 nmol] (99 +/- 6%, n = 6, P < 0.001). Injection of the reverse peptide, A<b eta>[35-25], also impaired LTP at concentrations of 10 nmol (136 +/- 3%, n = 6, P < 0.01) and 100 nmol (144 +/- 7, n = 8, P < 0.05). Using a different protocol, HFS was delivered 5 min following A beta injections, and LTP was measured 1 h post HFS. Stable LTP was produced in the control group (188 /- 15%, n = 7) and blocked by A beta [25-35, 100 nmol] (108 +/- 15%, n = 6, P < 0.001). A lower dose of A<beta>[25-35; 10 nmol] did not significantly impair LTP (176 +/- 30%, n = 4). The A beta -peptides tested were also show n to have no significant effect on paired pulse facilitation (interstimulus interval of 50 ms), suggesting that neither presynaptic transmitter releas e or activity of interneurons in vivo are affected. The effects of A beta o n LTP are therefore likely to be mediated via a postsynaptic mechanism. Thi s in vivo model of LTP is extremely sensitive to A beta -peptides that can impair LTP in a time- ([25-35]) and concentration-dependent manner ([25-35] and [35-25]). These effects of A beta -peptides may then contribute to the cognitive deficits associated with Alzheimer's disease.