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 Aβ-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.
Bibliographical noteFunding Information:
This work was supported by the Cullen Trust, the Alzheimer’s Drug Discovery Foundation (ADDF), and the Mitchell Center for Neurodegenerative Diseases. We thank Dr. Maxime Rousseaux for his suggestions and critical reading of the manuscript and Dr. Lindsay Reese of SciReviser for editing the manuscript. PSP tissues for this research were provided by the Johns Hopkins University Morris Udall Parkinson’s Disease Center of Excellence (NINDS P50 NS38377) and Alzheimer’s Disease Research Center (NIA P50 AG05146).
© 2014 Lasagna-Reeves et al.; licensee BioMed Central Ltd.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience