Formation and Propagation of Tau Oligomeric Seeds

Julia E Gerson,Rakez Kayed

doi:10.3389/fneur.2013.00093

Abstract

Tau misfolding and aggregation leads to the formation of neurofibrillary tangles (NFTs), which have long been considered one of the main pathological hallmarks for numerous neurodegenerative diseases known as tauopathies, including Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). However, recent studies completed both in vitro and in vivo suggest that intermediate forms of tau, known as tau oligomers, between the monomeric form and NFTs are the true toxic species in disease and the best targets for anti-tau therapies. However, the exact mechanism by which the spread of pathology occurs is unknown. Evidence suggests that tau oligomers may act as templates for the misfolding of native tau, thereby seeding the spread of the toxic forms of the protein. Recently, researchers have reported the ability of tau oligomers to enter and exit cells, propagating from disease-affected regions to unaffected areas. While the mechanism by which the spreading of misfolded tau occurs has yet to be elucidated, there are a few different models which have been proposed, including cell membrane stress and pore-formation, endocytosis and exocytosis, and non-traditional secretion of protein not enclosed by a membrane. Coming to an understanding of how toxic tau species seed and spread through the brain will be crucial to finding effective treatments for neurodegenerative tauopathies.

Highlights

Formation and propagation of tau oligomeric seedsReviewed by: Naruhiko Sahara, University of Florida, USA Irving E
TAU OLIGOMERS ARE THE TOXIC TAU SPECIES IN NEURODEGENERATIVE TAUOPATHIES The formation of tau aggregates and neurofibrillary tangles (NFTs) is one of the main pathological hallmarks of numerous diseases termed tauopathies, including the two most common neurodegenerative diseases, Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) [1, 2]
In primary neurons treated with tau oligomers, extracellular tau only increases once levels as high as 40% cell death are reached, which does not correspond to physiological levels of cell death during the initial spread of neurodegenerative disease [130]

Summary

Formation and propagation of tau oligomeric seeds

Reviewed by: Naruhiko Sahara, University of Florida, USA Irving E. Studies using the rTg4510 mouse model, which conditionally expresses P301L mutant tau, found that cell death occurred prior to NFT formation and that cell loss and behavioral impairments could be suppressed by inhibiting tau expression without removing NFTs or preventing their continued accumulation [7, 15] In accordance with this finding, it has been shown that NFTs are protective in the same mouse model [16], and only pro-aggregate human tau mice (TauRD) show behavioral deficits [17]. It is possible that NFTs are neuroprotective, sequestering toxic forms of tau into large aggregates with less flexibility and surface area to interact with cells All of these studies form the framework for the model of the progression of neurodegenerative tauopathies beginning with the seeding and propagation of toxic tau oligomers (Figure 1)

Propagation of oligomeric soluble tau aggregates

Findings

CONCLUSION