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Phosphorylation of the amyloid ?-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

ABSTRACT: Aggregation and toxicity of the amyloid ?-peptide (A?) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric A? assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the A? sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type A? remain unclear. Here, we identified an A? variant phosphorylated at Ser26 residue (pSer26A?) in transgenic mouse models of AD and in human brain that shows contrasting spatio-temporal distribution as compared to non-phosphorylated A? (npA?) or other modified A? species. pSer26A? is particularly abundant in intraneuronal deposits at very early stages of AD, but much less in extracellular plaques. pSer26A? assembles into a specific oligomeric form that does not proceed further into larger fibrillar aggregates, and accumulates in characteristic intracellular compartments of granulovacuolar degeneration together with TDP-43 and phosphorylated tau. Importantly, pSer26A? oligomers exert increased toxicity in human neurons as compared to other known A? species. Thus, pSer26A? could represent a critical species in the neurodegeneration during AD pathogenesis.

SUBMITTER: Kumar S

PROVIDER: S-EPMC4789232 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Phosphorylation of the amyloid β-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

Kumar Sathish S Wirths Oliver O Stüber Kathrin K Wunderlich Patrick P Koch Philipp P Theil Sandra S Rezaei-Ghaleh Nasrollah N Zweckstetter Markus M Bayer Thomas A TA Brüstle Oliver O Thal Dietmar R DR Walter Jochen J

Acta neuropathologica 20160222 4

Aggregation and toxicity of the amyloid β-peptide (Aβ) are considered as critical events in the initiation and progression of Alzheimer's disease (AD). Recent evidence indicated that soluble oligomeric Aβ assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aβ sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization o ...[more]

PMID: 26898910

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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the pathological aggregation of the amyloid-? peptide (A?). Monomeric soluble A? can switch from helicoidal to ?-sheet conformation, promoting its assembly into oligomers and subsequently to amyloid fibrils. Oligomers are highly toxic to neurons and have been reported to induce synaptic transmission impairments. The progression from oligomers to fibrils forming senile plaques is currently considered a protective mechanism to avoid the presence of the highly toxic oligomers. Protein nitration is a frequent post-translational modification under AD nitrative stress conditions. A? can be nitrated at tyrosine 10 (Y10) by peroxynitrite. Based on our analysis of ThT binding, Western blot and electron and atomic force microscopy, we report that A? nitration stabilizes soluble, highly toxic oligomers and impairs the formation of fibrils. We propose a mechanism by which fibril elongation is interrupted upon Y10 nitration: Nitration disrupts fibril-forming folds by preventing H14-mediated bridging, as shown with an A? analog containing a single residue (H to E) replacement that mimics the behavior of nitrated A? related to fibril formation and neuronal toxicity. The pathophysiological role of our findings in AD was highlighted by the study of these nitrated oligomers on mouse hippocampal neurons, where an increased NMDAR-dependent toxicity of nitrated A? oligomers was observed. Our results show that A? nitrotyrosination is a post-translational modification that increases A? synaptotoxicity. SIGNIFICANCE STATEMENT:We report that nitration (i.e., the irreversible addition of a nitro group) of the Alzheimer-related peptide amyloid-? (A?) favors the stabilization of highly toxic oligomers and inhibits the formation of A? fibrils. The nitrated A? oligomers are more toxic to neurons due to increased cytosolic calcium levels throughout their action on NMDA receptors. Sustained elevated calcium levels trigger excitotoxicity, a characteristic event in Alzheimer's disease.

Project description:Alzheimer's disease and Type 2 diabetes are pathological processes associated to ageing. Moreover, there are evidences supporting a mechanistic link between Alzheimer's disease and insulin resistance (one of the first hallmarks of Type 2 diabetes). Regarding Alzheimer's disease, amyloid β-peptide aggregation into β-sheets is the main hallmark of Alzheimer's disease. At monomeric state, amyloid β-peptide is not toxic but its function in brain, if any, is unknown. Here we show, by in silico study, that monomeric amyloid β-peptide 1-40 shares the tertiary structure with insulin and is thereby able to bind and activate insulin receptor. We validated this prediction experimentally by treating human neuroblastoma cells with increasing concentrations of monomeric amyloid β-peptide 1-40. Our results confirm that monomeric amyloid β-peptide 1-40 activates insulin receptor autophosphorylation, triggering downstream enzyme phosphorylations and the glucose Transporter 4 translocation to the membrane. On the other hand, neuronal insulin resistance is known to be associated to Alzheimer's disease since early stages. We thus modelled the docking of oligomeric amyloid β-peptide 1-40 to insulin receptor. We found that oligomeric amyloid β-peptide 1-40 blocks insulin receptor, impairing its activation. It was confirmed in vitro by observing the lack of insulin receptor autophosphorylation, and also the impairment of insulin-induced intracellular enzyme activations and the glucose Transporter 4 translocation to the membrane. By biological system analysis, we have carried out a mathematical model recapitulating the process that turns amyloid β-peptide binding to insulin receptor from the physiological to the pathophysiological regime. Our results suggest that monomeric amyloid β-peptide 1-40 contributes to mimic insulin effects in the brain, which could be good when neurons have an extra requirement of energy beside the well-known protective effects on insulin intracellular signalling, while its accumulation and subsequent oligomerization blocks the insulin receptor producing insulin resistance and compromising neuronal metabolism and protective pathways.

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Phosphorylation of the amyloid ?-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

Publications

Phosphorylation of the amyloid β-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity.

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