A beta and tau prion-like activities decline with longevity in the Alzheimer's disease human brain
| Autor: | Glenda M. Halliday, Carlo Condello, Sjoerd G. van Duinen, Lars Lannfelt, Stanley B. Prusiner, Joanne C. Lee, Weizhou Yue, C. Dirk Keene, Amanda L. Woerman, Brianna M. Rivera, Martin Ingelsson, William F. DeGrado, Atsushi Aoyagi, Jan Stöhr, Caroline Graff, Thomas D. Bird, William W. Seeley |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
medicine.medical_specialty Aging Genotype Prions Transgene media_common.quotation_subject Apolipoprotein E4 Longevity Mice Transgenic Plaque Amyloid tau Proteins Disease Biology Article Alzheimer Disease Internal medicine medicine Animals Humans Protein Isoforms Gliosis Phosphorylation media_common Aged Aged 80 and over Amyloid beta-Peptides HEK 293 cells Brain General Medicine Human brain Middle Aged Phenotype Disease Models Animal medicine.anatomical_structure Endocrinology HEK293 Cells Intracellular |
| Zdroj: | Sci Transl Med Science Translational Medicine, 11(490). AMER ASSOC ADVANCEMENT SCIENCE |
| Popis: | The hallmarks of Alzheimer's disease (AD) are the accumulation of A beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau. We developed sensitive cellular assays using human embryonic kidney-293T cells to quantify intracellular self-propagating conformers of A beta in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological A beta conformers. Individuals over 80 years of age had the lowest amounts of prion-like A beta and phosphorylated tau. Unexpectedly, the longevity-dependent decrease in self-propagating tau conformers occurred in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the ability of postmortem AD brain homogenates to induce misfolded tau in the cellular assays showed an exponential decrease with longevity, with a half-life of about one decade over the age range of 37 to 99 years. Thus, our findings demonstrate an inverse correlation between longevity in patients with AD and the abundance of pathological tau conformers. Our cellular assays can be applied to patient selection for clinical studies and the development of new drugs and diagnostics for AD. |
| Databáze: | OpenAIRE |
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