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

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.

New Insights Into the Pathogenesis of Alzheimer's Disease

“…Currently, cholinesterase inhibitors (AChEIs) and the NMDA receptor antagonist are the only therapies for AD (76). However, these can only relieve symptoms and not delay the progress of AD (77)(78)(79). Moreover, three cholinesterase inhibitors, namely, donepezil, rivastigmine, and galantamine, which are approved by the US Food and Drug Administration, were proven to increase side effects, such as nausea, vomiting, and diarrhea.…”

Virulent Pseudomonas aeruginosa infection converts antimicrobial amyloids into cytotoxic prions

“…37 A self-propagating protein, or prion, should be able to replicate in cell culture and pass from one naïve cell population to another while retaining its pathological characteristics. [63][64][65] However, the potential of ExoY, alone or in conjunction with other T3SS effectors, to generate selfpropagating amyloid cytotoxins has not been determined.…”

Experimental models of prion‐like protein propagation

“…Aoyagi et al established a cellular model of tau aggregation by introducing concentrated abnormal tau proteins from AD brains, and reported that insoluble tau from the early stage of AD has a higher seeding activity than that from later stages. 27 Mouse models of tau propagation were developed in 2009 by Clavaguera et al 28 They showed that inoculation of brain homogenates prepared from P301S tau transgenic mice with inclusions into tau mice overexpressing wild-type human tau induced tau pathologies. They also showed that brain homogenates prepared from brains of patients induce tau pathologies in mice similar to those in © 2020 Japanese Society of Neuropathology…”