Research ResourceAlzheimer’s Disease

Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain

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Science Translational Medicine  01 May 2019:
Vol. 11, Issue 490, eaat8462
DOI: 10.1126/scitranslmed.aat8462

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Puncta point the way

Amyloid plaques composed of Aβ peptides and neurofibrillary tangles composed of aberrant tau proteins are the key pathological hallmarks in the Alzheimer’s disease (AD) brain. However, understanding which conformers of Aβ and tau play a pathological role at each step of AD pathogenesis has been difficult to elucidate. Aoyagi et al. have developed sensitive cellular assays that detect aberrant Aβ and tau in postmortem brain homogenates from patients with AD or other neurodegenerative diseases. Using fluorescent puncta as a readout, these assays now reveal that patients with AD who died at an older age have lower Aβ and tau pathological conformers than do patients who died at a younger age.

Abstract

The hallmarks of Alzheimer’s disease (AD) are the accumulation of Aβ 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 Aβ in brain samples from patients with AD or other neurodegenerative diseases. Postmortem brain tissue from patients with AD had measurable amounts of pathological Aβ conformers. Individuals over 80 years of age had the lowest amounts of prion-like Aβ 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.

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