| First Author | Grochowska KM | Year | 2017 |
| Journal | EMBO Rep | Volume | 18 |
| Issue | 6 | Pages | 962-981 |
| PubMed ID | 28420656 | Mgi Jnum | J:243595 |
| Mgi Id | MGI:5909174 | Doi | 10.15252/embr.201643519 |
| Citation | Grochowska KM, et al. (2017) Posttranslational modification impact on the mechanism by which amyloid-beta induces synaptic dysfunction. EMBO Rep 18(6):962-981 |
| abstractText | Oligomeric amyloid-beta (Abeta) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Abeta have been identified, among which N-terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms. Here, we show that a prominent isoform, pyroglutamated Abeta3(pE)-42, induces synaptic dysfunction to a similar extent like Abeta1-42 but by clearly different mechanisms. In contrast to Abeta1-42, Abeta3(pE)-42 does not directly associate with synaptic membranes or the prion protein but is instead taken up by astrocytes and potently induces glial release of the proinflammatory cytokine TNFalpha. Moreover, Abeta3(pE)-42-induced synaptic dysfunction is not related to NMDAR signalling and Abeta3(pE)-42-induced impairment of synaptic plasticity cannot be rescued by D1-agonists. Collectively, the data point to a scenario where neuroinflammatory processes together with direct synaptotoxic effects are caused by posttranslational modification of soluble oligomeric Abeta and contribute synergistically to the onset of synaptic dysfunction in AD. |
