Publikationsdatum:
2012-06-05
Beschreibung:
Extracellular plaques of amyloid-beta and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-beta 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-beta. Interestingly, many adverse responses to amyloid-beta, 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-beta are strongly associated with Alzheimer's disease, are more toxic than amyloid-beta, residues 1-42 (Abeta(1-42)) and Abeta(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Abeta may trigger Alzheimer's disease. Abeta(3(pE)-42) co-oligomerizes with excess Abeta(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 Abeta(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Abeta(3(pE)-42) plus 95% Abeta(1-42) (5% pE-Abeta) seed new cytotoxic LNOs through multiple serial dilutions into Abeta(1-42) monomers in the absence of additional Abeta(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Abeta(3(pE)-42), and enhanced Abeta(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Abeta(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Abeta(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Abeta(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367389/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nussbaum, Justin M -- Schilling, Stephan -- Cynis, Holger -- Silva, Antonia -- Swanson, Eric -- Wangsanut, Tanaporn -- Tayler, Kaycie -- Wiltgen, Brian -- Hatami, Asa -- Ronicke, Raik -- Reymann, Klaus -- Hutter-Paier, Birgit -- Alexandru, Anca -- Jagla, Wolfgang -- Graubner, Sigrid -- Glabe, Charles G -- Demuth, Hans-Ulrich -- Bloom, George S -- GM008136/GM/NIGMS NIH HHS/ -- P50 AG016573/AG/NIA NIH HHS/ -- P50AG16573/AG/NIA NIH HHS/ -- R01 AG033069/AG/NIA NIH HHS/ -- R01AG033069/AG/NIA NIH HHS/ -- T32 GM008136/GM/NIGMS NIH HHS/ -- T32 GM008136-25/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 May 2;485(7400):651-5. doi: 10.1038/nature11060.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Virginia, Charlottesville, Virginia 22904, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22660329" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Alzheimer Disease/metabolism
;
Amyloid/chemistry/drug effects/metabolism/*toxicity
;
Amyloid beta-Peptides/*chemistry/genetics/metabolism/toxicity
;
Animals
;
Disease Models, Animal
;
Glutamic Acid/chemistry/*metabolism
;
Humans
;
Mice
;
Mice, Transgenic
;
Mutant Proteins/*chemistry/genetics/metabolism/*toxicity
;
Peptide Fragments/*chemistry/genetics/metabolism/toxicity
;
Prions/chemistry/*metabolism/toxicity
;
tau Proteins/deficiency/genetics/*metabolism
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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