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Title

Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease

Authors
Dujardin, Simon
Commins, Caitlin
Beerepoot, Pieter
Fernandes, Analiese R
Kamath, Tarun V
De Los Santos, Mark B
Klickstein, Naomi
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Published in Nature medicine. 2020, vol. 26, no. 8, p. 1256-1263
Abstract 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.
Keywords Age of OnsetAgedAged, 80 and overAlzheimer Disease / geneticsAlzheimer Disease / metabolismAlzheimer Disease / pathologyCerebral Cortex / metabolismCerebral Cortex / pathologyCognitive Dysfunction / geneticsCognitive Dysfunction / pathologyFemaleGenetic HeterogeneityHumansMaleMiddle AgedNeurofibrillary Tangles / geneticsNeurofibrillary Tangles / metabolismNeurofibrillary Tangles / pathologyPhosphorylationProtein Aggregation, Pathological / geneticsProtein Aggregation, Pathological / pathologySeverity of Illness IndexTau Proteins / genetics
Identifiers
PMID: 32572268
PMCID: PMC7603860
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Project
Swiss National Science Foundation: P2ELP3_184403
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(ISO format)
DUJARDIN, Simon et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease. In: Nature medicine, 2020, vol. 26, n° 8, p. 1256-1263. doi: 10.1038/s41591-020-0938-9 https://archive-ouverte.unige.ch/unige:155608

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Deposited on : 2021-10-21

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