Tau molecular diversity mediates clinical heterogeneity in Alzheimer’s disease

ABSTRACT: Alzheimer’s disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins varied across individuals. We carried out biochemical, biophysical, and both cell- and animal-based bioactivity assays, and mass spectrometry, to characterize tau in 32 AD patients. 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 sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, while 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 cancer patients, may have multiple molecular drivers of an otherwise common phenotype, and emphasizes the potential for personalized therapeutic approaches for slowing clinical progression in AD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Pieter Beerepoot  

LAB HEAD: Judith Steen

PROVIDER: PXD018855 | Pride | 2020-08-09

REPOSITORIES: Pride