Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction

TY - JOUR

T1 - Posttranslational modification impact on the mechanism by which amyloid-β induces synaptic dysfunction

AU - Grochowska, Katarzyna M

AU - Yuanxiang, PingAn

AU - Bär, Julia

AU - Raman, Rajeev

AU - Brugal, Gemma

AU - Sahu, Giriraj

AU - Schweizer, Michaela

AU - Bikbaev, Arthur

AU - Schilling, Stephan

AU - Demuth, Hans-Ulrich

AU - Kreutz, Michael R

N1 - © 2017 The Authors.

PY - 2017/6

Y1 - 2017/6

N2 - Oligomeric amyloid-β (Aβ) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ 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 Aβ3(pE)-42, induces synaptic dysfunction to a similar extent like Aβ1-42 but by clearly different mechanisms. In contrast to Aβ1-42, Aβ3(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 TNFα. Moreover, Aβ3(pE)-42-induced synaptic dysfunction is not related to NMDAR signalling and Aβ3(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 Aβ and contribute synergistically to the onset of synaptic dysfunction in AD.

AB - Oligomeric amyloid-β (Aβ) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ 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 Aβ3(pE)-42, induces synaptic dysfunction to a similar extent like Aβ1-42 but by clearly different mechanisms. In contrast to Aβ1-42, Aβ3(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 TNFα. Moreover, Aβ3(pE)-42-induced synaptic dysfunction is not related to NMDAR signalling and Aβ3(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 Aβ and contribute synergistically to the onset of synaptic dysfunction in AD.

KW - Journal Article

U2 - 10.15252/embr.201643519

DO - 10.15252/embr.201643519

M3 - SCORING: Journal article

C2 - 28420656

VL - 18

SP - 962

EP - 981

JO - EMBO REP

JF - EMBO REP

SN - 1469-221X

IS - 6

ER -