Abstract
Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD.
Highlights
Alzheimer’s disease (AD), similar to several other aggregation-associated neurodegenerative diseases [1, 2], is characterized by a progressive decline in health over the course of several years, with symptoms often only becoming apparent years after the onset of pathological changes in the brain
Synthetic tau filaments made from recombinant protein and filamentous material extracted from tau mouse models or AD brains have been shown to act as seeds in various model systems and initiate tau pathology [5,6,7,8,9]
Several mouse model systems provide evidence that seeds spread from the regions in which they are initially formed to other regions of the brain and trigger aggregation there [5, 10,11,12]
Summary
Alzheimer’s disease (AD), similar to several other aggregation-associated neurodegenerative diseases [1, 2], is characterized by a progressive decline in health over the course of several years, with symptoms often only becoming apparent years after the onset of pathological changes in the brain. While A aggregation is believed to be an important event in the development of AD, clinical symptoms, atrophy, and brain damage correlate best with the appearance of tau aggregates [4]. Several mouse model systems provide evidence that seeds spread from the regions in which they are initially formed to other regions of the brain and trigger aggregation there [5, 10,11,12]. The molecular processes that lead to tau seed replication and spreading are not known in detail but, based on animal models, are postulated to involve aggregation, transport down axons, release, uptake, and, replication in the recipient neuron
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