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Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease.
Dujardin, Simon; Commins, Caitlin; Lathuiliere, Aurelien; Beerepoot, Pieter; Fernandes, Analiese R; Kamath, Tarun V; De Los Santos, Mark B; Klickstein, Naomi; Corjuc, Diana L; Corjuc, Bianca T; Dooley, Patrick M; Viode, Arthur; Oakley, Derek H; Moore, Benjamin D; Mullin, Kristina; Jean-Gilles, Dinorah; Clark, Ryan; Atchison, Kevin; Moore, Renee; Chibnik, Lori B; Tanzi, Rudolph E; Frosch, Matthew P; Serrano-Pozo, Alberto; Elwood, Fiona; Steen, Judith A; Kennedy, Matthew E; Hyman, Bradley T.
Afiliación
  • Dujardin S; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Commins C; Harvard Medical School, Boston, MA, USA.
  • Lathuiliere A; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Beerepoot P; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Fernandes AR; Harvard Medical School, Boston, MA, USA.
  • Kamath TV; Harvard Medical School, Boston, MA, USA.
  • De Los Santos MB; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • Klickstein N; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Corjuc DL; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Corjuc BT; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Dooley PM; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Viode A; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Oakley DH; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Moore BD; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Mullin K; C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
  • Jean-Gilles D; Harvard Medical School, Boston, MA, USA.
  • Clark R; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • Atchison K; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Moore R; Harvard Medical School, Boston, MA, USA.
  • Chibnik LB; C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, USA.
  • Tanzi RE; Alzheimer Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Frosch MP; Harvard Medical School, Boston, MA, USA.
  • Serrano-Pozo A; Aquinnah Pharmaceuticals, Cambridge, MA, USA.
  • Elwood F; Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
  • Steen JA; Department of Neuroscience, Merck & Co., Boston, MA, USA.
  • Kennedy ME; Department of Neuroscience, Merck & Co., Boston, MA, USA.
  • Hyman BT; Department of Neuroscience, Merck & Co., Boston, MA, USA.
Nat Med ; 26(8): 1256-1263, 2020 08.
Article en En | MEDLINE | ID: mdl-32572268
Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Enfermedad de Alzheimer / Disfunción Cognitiva / Agregación Patológica de Proteínas Límite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas tau / Enfermedad de Alzheimer / Disfunción Cognitiva / Agregación Patológica de Proteínas Límite: Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos