Abstract: In Alzheimer's disease (AD), β-amyloid peptides aggregate to form amyloid plaques, and the microtubule-associated protein tau forms neurofibrillary tangles. However, severity and duration of AD correlate with the stereotypical emergence of tau tangles throughout the brain, suggestive of a gradual region-to-region spreading of pathological tau. The current notion in the field is that misfolded tau seeds propagate transsynaptically and corrupt the proper folding of soluble tau in recipient neurons. This is supported by accumulating evidence showing that in AD, functional connectivity and not proximity predicts the spreading of tau pathology. Tau seeds can be found in two flavors, vesicle-free, that is, naked as in oligomers and fibrils, or encapsulated by membranes of secreted vesicles known as exosomes. Both types of seeds have been shown to propagate between interconnected neurons. Here, we describe potential ways of how their propagation can be controlled in several subcellular compartments by manipulating mechanisms affecting production, neuron-to-neuron transmission, internalization, endosomal escape, and autophagy. We emphasize that although vesicle-free tau seeds and exosomes differ, they share the ability to trigger endolysosomal permeabilization. Such a mechanistic convergence in endolysosomal permeabilization presents itself as a unique opportunity to target both types of tau seeding. We discuss the cellular response to endolysosomal damage that might be key to control permeabilization, and the significant overlap in the seeding mechanism of proteopathic agents other than tau, which suggests that targeting the endolysosomal pathway could pave the way toward developing broad-spectrum treatments for neurodegenerative diseases.
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