Abstract
Pathological aggregation of the microtubule-associated protein tau and subsequent accumulation of neurofibrillary tangles (NFTs) or other tau-containing inclusions are defining histopathological features of many neurodegenerative diseases, which are collectively known as tauopathies. Due to conflicting results regarding a correlation between the presence of NFTs and disease progression, the mechanism linking pathological tau aggregation with cell death is poorly understood. An emerging view is that NFTs are not the toxic entity in tauopathies; rather, tau intermediates between monomers and NFTs are pathogenic. Several proteins associated with neurodegenerative diseases, such as β-amyloid (Aβ) and α-synuclein, have the tendency to form pore-like amyloid structures (annular protofibrils, APFs) that mimic the membrane-disrupting properties of pore-forming protein toxins. The present study examined the similarities of tau APFs with other tau amyloid species and showed for the first time the presence of tau APFs in brain tissue from patients with progressive supranuclear palsy (PSP) and dementia with Lewy bodies (DLB), as well as in the P301L mouse model, which overexpresses mutated tau. Furthermore, we found that APFs are preceded by tau oligomers and do not go on to form NFTs, evading fibrillar fate. Collectively, our results demonstrate that in vivo APF formation depends on mutations in tau, phosphorylation levels, and cell type. These findings establish the pathological significance of tau APFs in vivo and highlight their suitability as therapeutic targets for several neurodegenerative tauopathies.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-56) contains supplementary material, which is available to authorized users.
Highlights
The microtubule-associated protein tau plays important cellular roles, including regulating microtubule assembly and stability, axonal transport, and neurite outgrowth [1]
When liposomes were reconstituted with tau oligomers and incubated for 2 h, annular protofibrils (APFs) were detected by atomic force microscopy (AFM) (Additional file 1: Figure S1a)
As we previously reported for Aβ and α-synuclein [31], tau APFs are less toxic than the oligomers used to prepared them
Summary
The microtubule-associated protein tau plays important cellular roles, including regulating microtubule assembly and stability, axonal transport, and neurite outgrowth [1]. Soluble oligomers have been implicated as the primary toxic species in many degenerative diseases in which the accumulation of large fibrillar deposits may be inert, protective, or pathological by a different mechanism [18,19]. Their structures, interrelationships with other amyloid aggregates, and exact contribution to disease pathogenesis are not entirely clear [20,21,22,23]. The formation of pores by Aβ and α-synuclein aggregates are accelerated when the APFs are generated using proteins with mutations associated with familial Alzheimer’s and Parkinson’s diseases, respectively, suggesting that these mutated proteins are more prone to pathogenic activity [26]. The off pathway conversion of oligomers to APFs, which penetrate the membrane, is an attractive explanation for this toxic effect given the shared assembly state and morphological resemblance between APFs and bacterial pores
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