The action of naturally secreted cell-derived Alzheimer’s disease β-amyloid (Aβ) and synthetic Ab1-42 were investigated on the induction of LTP in the rat medial perforant path to dentate granule cell synapse in vitro.

The animals were humanely killed. Both cell-derived and synthetic Aβ strongly inhibited high frequency stimulation (HFS)-induced LTP. In control slices in physiological media, HFS induced LTP measuring 151 ± 6 % (mean ± S.E.M.) at 60 min post-HFS (P < 0.005, n = 8, Student’s unpaired t test). In the presence of synthetic Aβ (200 nM), LTP induction measured 115 ± 7 % (P < 0.005, n = 8). In the presence of conditioned medium containing cell-derived Aβ collected from 7PA2 cells secreting nanomolar concentrations of soluble Aβ, LTP induction measured 110 ± 7 %, n = 6 P < 0.005, compared with 188 ± 10 %, n = 6, in control medium collected from non-transfected CHO cells. Baseline transmission was not altered by synthetic or cell-derived Aβ. The involvement of metabotropic glutamate receptors (mGluRs) in the Aβ-mediated block of LTP induction was investigated by applying Aβ in the presence of the group I/II mGluR antagonist LY341495 and the mGluR5 antagonist MPEP. Both antagonists prevented the inhibition of LTP induction by synthetic Aβ, LTP measuring 147 ± 3 % and 141 ± 9 %, respectively, n = 5, P < 0.005. In addition, the group I mGluR agonist DHPG lowered the threshold concentration for the inhibitory action of Aβ. Thus 100 nM synthetic Aβ was found to inhibit LTP induction in the presence of the selective group I agonist DHPG (20 µM) (129 ± 4 %, P < 0.005, n = 5), but not in control media (146 ± 10 %, n = 5).