O1‐07‐05: Paired helical filaments from Alzheimer's disease brains induce the intracellular accumulation of tau in aggresomes: Novel therapeutic approaches to prevent the propagation and spreading of tau pathology

Abstract

Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer's disease (AD) and tauopathies. The specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated, it propagates between neighboring neuronal cells, possibly spreading along axonal networks. In other words, misfolded aggregated tau protein released by degenerating neurons can mediate and spread toxicity to neighboring cells. We studied whether PHFs could be taken up by cells and promote the spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green-fluorescent protein tagged tau (GFP-Tau) were treated with isolated fractions of human AD-derived PHFs for 24 hours. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was made particularly evident by the perinuclear localization of aggregates and the re-distribution of vimentin intermediate filament networks and retrograde motor protein dynein. Furthermore, the content of Sarcosylinsoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. Exosome related mechanisms did not appear to be involved in the release of GFP-Tau from untreated cells. Paired helical filaments can mediate the spreading of pathological tau aggregation. Paired helical filament-mediated formation of aggresome-like bodies may be important in neurodegeneration. The evidence that cells can internalize PHFs leading to the formation of aggresome-like bodies opens new therapeutic avenues to prevent the propagation and spreading of tau pathology.