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

Abstract

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.

Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer’s Disease

“…S6B-D). These results are in line with previous evidence showing that amyloid-β oligomers induce translocation of non-phosphorylated Jacob to the nucleus (30)(31)(32).…”

“…By yet unknown mechanisms this signalosome promotes CREB phosphorylation at serine 133 and hence CREB dependent gene expression. On the contrary, activation of extrasynaptic NMDAR using bath NMDA or exogenous Aβ application leads to prominent translocation of nonphosphorylated Jacob and induces CREB shut-off followed by stripping of synaptic contacts, simplification of dendritic arborization and cell death (30)(31)(32). Taken together the data indicate that Jacob operates as a mobile hub that docks NMDAR-derived signalosomes to nuclear target sites (27,28).…”

“…CREB shut-off is a hallmark of AD (18,19,(21)(22)(23)(24)(25) and our previous studies indicate that Jacob plays a role in Aβ-induced CREB shut-off that is elicited by activation of extrasynaptic GluN2B containing NMDAR (30)(31)(32). In the brain of AD patients, Aβ oligomers can be found in various, post-translationally modified forms (41), out of which the N-terminally truncated, pyroglutamylated Aβ 3(pE)-42 species are very prominent (42)(43)(44)(45)(46)(47).…”

“…In the brain of AD patients, Aβ oligomers can be found in various, post-translationally modified forms (41), out of which the N-terminally truncated, pyroglutamylated Aβ 3(pE)-42 species are very prominent (42)(43)(44)(45)(46)(47). Aβ and Aβ 3(pE)-42 -induced CREB shut-off cause the impairment of synaptic function with subsequent synapse loss via different pathways that converge on nuclear import of nonphophorylated Jacob (31). In accordance with this previous work shRNA knockdown of Jacob (27)…”

“…Human Aβ oligomers (Anaspec, Cat#AS-20276) were prepared and characterized as described previously (31). Briefly, the lyophilised Aβ1-42 was incubated in…”