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000136529 0247_ $$2doi$$a10.1038/nature11060
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000136529 037__ $$aDZNE-2020-02851
000136529 041__ $$aEnglish
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000136529 1001_ $$0P:(DE-HGF)0$$aNussbaum, Justin M$$b0
000136529 245__ $$aPrion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β.
000136529 260__ $$aLondon [u.a.]$$bNature Publ. Group65848$$c2012
000136529 264_1 $$2Crossref$$3online$$bSpringer Science and Business Media LLC$$c2012-05-02
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000136529 520__ $$aExtracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.
000136529 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000136529 542__ $$2Crossref$$i2012-05-01$$uhttp://www.springer.com/tdm
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000136529 650_7 $$2NLM Chemicals$$aAmyloid
000136529 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000136529 650_7 $$2NLM Chemicals$$aMutant Proteins
000136529 650_7 $$2NLM Chemicals$$aPeptide Fragments
000136529 650_7 $$2NLM Chemicals$$aPrions
000136529 650_7 $$2NLM Chemicals$$aamyloid beta-protein (1-42)
000136529 650_7 $$2NLM Chemicals$$atau Proteins
000136529 650_7 $$03KX376GY7L$$2NLM Chemicals$$aGlutamic Acid
000136529 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000136529 650_2 $$2MeSH$$aAmyloid: chemistry
000136529 650_2 $$2MeSH$$aAmyloid: drug effects
000136529 650_2 $$2MeSH$$aAmyloid: metabolism
000136529 650_2 $$2MeSH$$aAmyloid: toxicity
000136529 650_2 $$2MeSH$$aAmyloid beta-Peptides: chemistry
000136529 650_2 $$2MeSH$$aAmyloid beta-Peptides: genetics
000136529 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000136529 650_2 $$2MeSH$$aAmyloid beta-Peptides: toxicity
000136529 650_2 $$2MeSH$$aAnimals
000136529 650_2 $$2MeSH$$aDisease Models, Animal
000136529 650_2 $$2MeSH$$aGlutamic Acid: chemistry
000136529 650_2 $$2MeSH$$aGlutamic Acid: metabolism
000136529 650_2 $$2MeSH$$aHumans
000136529 650_2 $$2MeSH$$aMice
000136529 650_2 $$2MeSH$$aMice, Transgenic
000136529 650_2 $$2MeSH$$aMutant Proteins: chemistry
000136529 650_2 $$2MeSH$$aMutant Proteins: genetics
000136529 650_2 $$2MeSH$$aMutant Proteins: metabolism
000136529 650_2 $$2MeSH$$aMutant Proteins: toxicity
000136529 650_2 $$2MeSH$$aPeptide Fragments: chemistry
000136529 650_2 $$2MeSH$$aPeptide Fragments: genetics
000136529 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000136529 650_2 $$2MeSH$$aPeptide Fragments: toxicity
000136529 650_2 $$2MeSH$$aPrions: chemistry
000136529 650_2 $$2MeSH$$aPrions: metabolism
000136529 650_2 $$2MeSH$$aPrions: toxicity
000136529 650_2 $$2MeSH$$atau Proteins: deficiency
000136529 650_2 $$2MeSH$$atau Proteins: genetics
000136529 650_2 $$2MeSH$$atau Proteins: metabolism
000136529 7001_ $$0P:(DE-HGF)0$$aSchilling, Stephan$$b1
000136529 7001_ $$0P:(DE-HGF)0$$aCynis, Holger$$b2
000136529 7001_ $$0P:(DE-HGF)0$$aSilva, Antonia$$b3
000136529 7001_ $$0P:(DE-HGF)0$$aSwanson, Eric$$b4
000136529 7001_ $$0P:(DE-HGF)0$$aWangsanut, Tanaporn$$b5
000136529 7001_ $$0P:(DE-HGF)0$$aTayler, Kaycie$$b6
000136529 7001_ $$0P:(DE-HGF)0$$aWiltgen, Brian$$b7
000136529 7001_ $$0P:(DE-HGF)0$$aHatami, Asa$$b8
000136529 7001_ $$0P:(DE-2719)2321269$$aRönicke, Raik$$b9$$udzne
000136529 7001_ $$0P:(DE-2719)2740485$$aReymann, Klaus$$b10$$udzne
000136529 7001_ $$0P:(DE-HGF)0$$aHutter-Paier, Birgit$$b11
000136529 7001_ $$0P:(DE-HGF)0$$aAlexandru, Anca$$b12
000136529 7001_ $$0P:(DE-HGF)0$$aJagla, Wolfgang$$b13
000136529 7001_ $$0P:(DE-HGF)0$$aGraubner, Sigrid$$b14
000136529 7001_ $$0P:(DE-HGF)0$$aGlabe, Charles G$$b15
000136529 7001_ $$0P:(DE-HGF)0$$aDemuth, Hans-Ulrich$$b16
000136529 7001_ $$0P:(DE-HGF)0$$aBloom, George S$$b17$$eCorresponding author
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