Characterization of tau oligomeric seeds in progressive supranuclear palsy

Abstract

BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative tauopathy which is primarily defined by the deposition of tau into globose-type neurofibrillary tangles (NFT). Tau in its native form has important functions for microtubule dynamics. Tau undergoes alternative splicing in exons 2, 3, and 10 which results in six different isoforms. Products of splicing on exon 10 are the most prone to mutations. Three repeat (3R) and four repeat (4R) tau, like other disease-associated amyloids, can form oligomers which may then go on to further aggregate and form fibrils. Recent studies from our laboratory and others have provided evidence that tau oligomers, not NFTs, are the most toxic species in neurodegenerative tauopathies and seed the pathological spread of tau.ResultsAnalysis of PSP brain sections revealed globose-type NFTs, as well as both phosphorylated and unphosphorylated tau oligomers. Analysis of PSP brains via Western blot and ELISA revealed the presence of increased levels of tau oligomers compared to age-matched control brains. Oligomers were immunoprecipitated from PSP brain and were capable of seeding the oligomerization of both 3R and 4R tau isoforms.ConclusionsThis is the first time tau oligomers have been characterized in PSP. These results indicate that tau oligomers are an important component of PSP pathology, along with NFTs. The ability of PSP brain-derived tau oligomers to seed 3R and 4R tau suggests that these oligomers represent the pathological species responsible for disease propagation and the presence of oligomers in a pure neurodegenerative tauopathy implies a common neuropathological process for tau seen in diseases with other amyloid proteins.

Tau oligomers in cerebrospinal fluid in Alzheimer's disease

“…We have previously demonstrated that tau oligomers also act as the pathological species in the disease progression of progressive supranuclear palsy (PSP) patients 40. Moreover, tau oligomers have been identified in cortical and striatal brain regions in patients with other amyloid diseases, such as Huntington's disease 41.…”

Tau Oligomers Derived from Traumatic Brain Injury Cause Cognitive Impairment and Accelerate Onset of Pathology in Htau Mice

“…Therefore, more useful information relevant to TBI and increased incidence of AD could be gleaned using mice that do not express mutated tau leading to drastic neurodegeneration phenotypes early in age. Previously, we isolated oligomers from brains that had AD and other tauopathies 27,36,44 and found that tau oligomers injected in WT mice exhibit toxic effects that can be protected with tau oligomer-specific antibodies, whereas treatment with tau monomer and fibrils does not lead to any phenotypic differences. 27,30 However, WT mice maintain protection after antibody treatment for significantly longer periods than mice expressing human tau rather than mouse tau.…”

“…In order to correct the level of fluorescence for background and cell size, the background multiplied by the area of the cell was subtracted from the total fluorescence, as described previously. 36 The corrected cell fluorescence was analyzed by one-way analysis of variance (ANOVA).…”

Neuronal network disintegration: common pathways linking neurodegenerative diseases

“…85 In PSP and CBD, with such obvious glial tau pathology, this may be a more dominant mechanism and the tau oligomers are considered as most responsible for the spread of pathology through the brain. 86 It is potentially possible that susceptibility of specific cells to specific proteinaceous material may vary, and this along with the susceptibility of various functional networks may be responsible for the heterogeneity of clinical phenotypes as well as their overlap. Why some clinical phenotypic networks (eg, the behavioural network) may be susceptible to several proteins (eg, tau and TDP-43) while the primary motor network, as in ALS, seems more susceptible to only TDP-43 pathology remains elusive.…”