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. Author manuscript; available in PMC: 2019 Jun 14.
Published in final edited form as: Nature. 2015 Aug 31;526(7573):443–447. doi: 10.1038/nature14864

Figure 3. Aη-α impairs hippocampal LTP.

Figure 3

a, In membrane lysates of brains obtained from BACE inhibitor (BI, 100mg/kg SCH1682496) treated animals an increase in CTF-η was observed, which was paralleled by a strong reduction of CTF-β, while CTF-α was unchanged (left panel). APP-FL and BACE1 signals remained unchanged (asterisk indicates background band). Calnexin served as a loading control (Left panel). In the soluble fraction BACE inhibition resulted in enhanced production of Aη-α species which was detected by antibody M3.2 (right panel). Reduced sAPP-β levels indicated efficient BACE1 inhibition. revealed a 95,4% increase upon BACE1 inhibition, n=3; p < 0.01, Student`s t-test). b-c, Pharmacological inhibition of BACE lowers hippocampal LTP. Three hours after a single gavage of SCH1682496 (100 mg/kg) or vehicle, hippocampal slices were cut and baseline transmission and LTP measured. Note, that compared to vehicle treated controls in slices from inhibitor treated mice LTP was notably reduced. c, Representative fEPSPs recorded in CA1 area prior and 45 min after tetanization of Schaffer collaterals (top) with summary plots of the effects of the inhibitor and vehicle on fEPSP slopes in all examined groups. d, Soluble Aη-α and Aη-β peptides were expressed in CHO cells. Conditioned media were analyzed with antibodies 2D8, 2E9 and 9478D for the presence of the larger Aη-α and the smaller Aη-β peptides. e-h, SEC fractions containing Aη were diluted (1:15) in ACSF for the treatment of hippocampal slices and LTP measurements. Aη-α or Aη-β and control SEC fractions (obtained from CHO cells transfected with the empty vector) were perfused over mouse hippocampal slices for 20 min after obtaining a stable baseline of a fEPSP at the CA3-CA1 synapse. After 20 minutes a high-frequency stimulation protocol was applied (HFS; 2x (100 Hz, 1 s) at 20 second inter-stimulus interval) to induce long-term potentiation (LTP). e, Supernatants from CHO cells expressing Aη-α significantly inhibited LTP; f, Supernatants from CHO cells expressing Aη-β did not alter LTP. g, Supernatants from untransfected CHO cells did not alter LTP when compared to the control condition (ACSF only); h, summary graph of LTP magnitudes (as % of baseline) calculated 45-60 minutes post-HFS from graphs in e-g with statistical analysis (*p < 0.05); error bars represent s.e.m. n = number of fields. For each condition, sample fEPSP traces pre-LTP (black) and 45-60 min post-LTP (grey) induction are shown.