Abstract
BackgroundMicrotubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer’s disease and several other neurodegenerative diseases. Tau mutations are associated with frontotemperal dementia with parkinsonism on chromosome 17 (FTDP-17). rTg4510 mice overexpress human tau carrying the P301L FTDP-17 mutation and develop robust NFT-like pathology at 4–5 months of age. The current study is aimed at characterizing the rTg4510 mice to better understand the genesis of tau pathology and to better enable the use of this model in drug discovery efforts targeting tau pathology.ResultsUsing a panel of immunoassays, we analyzed the age-dependent formation of pathological tau in rTg4510 mice and our data revealed a steady age-dependent accumulation of pathological tau in the insoluble fraction of brain homogenates. The pathological tau was associated with multiple post-translational modifications including aggregation, phosphorylation at a wide variety of sites, acetylation, ubiquitination and nitration. The change of most tau species reached statistical significance at the age of 16 weeks. There was a strong correlation between the different post-translationally modified tau species in this heterogeneous pool of pathological tau. Total tau in the cerebrospinal fluid (CSF) displayed a multiphasic temporal profile distinct from the steady accumulation of pathological tau in the brain. Female rTg4510 mice displayed significantly more aggressive accumulation of pathological tau in the brain and elevation of total tau in CSF than their male littermates.ConclusionThe immunoassays described here were used to generate the most comprehensive description of the changes in various tau species across the lifespan of the rTg4510 mouse model. The data indicate that development of tauopathy in rTg4510 mice involves the accumulation of a pool of pathological tau that carries multiple post-translational modifications, a process that can be detected well before the histological detection of NFTs. Therapeutic treatment targeting tau should therefore aim to reduce all tau species associated with the pathological tau pool rather than reduce specific post-translational modifications. There is still much to learn about CSF tau in physiological and pathological processes in order to use it as a translational biomarker in drug discovery.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0011-1) contains supplementary material, which is available to authorized users.
Highlights
Microtubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer’s disease and several other neurodegenerative diseases
The second type of p-tau, as detected by antibodies AT270, pS400, pS404 and pS412, displayed a profile similar to that of total tau, i.e., a decrease in the soluble fraction, an increase in the insoluble fraction and a transition from a 55 kD to a 64 kD species in the insoluble fraction as the animals aged (Figure 1C). These data are consistent with observations from other groups and demonstrate an age-dependent development and accumulation of a 64 kD species of pathological tau that is enriched in the insoluble fraction of brain extracts and correlates with the development of tauopathy, neuronal cell loss, brain atrophy and cognitive impairment [10]
The 64 kD tau cannot be said to comprise only one or even a few p-tau species, but rather encompasses the global phosphorylation of tau at all epitopes studied. These data suggest that the accumulation of 64 kD tau in the insoluble fraction can be used as a surrogate marker to monitor tauopathy development and that a treatment reducing pathological tau formation should lead to a correlative reduction of all tau species associated with tauopathy
Summary
Microtubule associated protein tau is the major component of the neurofibrillary tangles (NFTs) found in the brains of patients with Alzheimer’s disease and several other neurodegenerative diseases. Pathological tau in AD brain is hyperphosphorylated and forms insoluble aggregates that eventually develop into NFTs [2]. This observation has led to the hypothesis that abnormal phosphorylation plays a major role in the disease process. Tau is present in cerebral spinal fluid (CSF) and tau in CSF is elevated in AD patients long before the clinical symptoms of the disease are manifest [6]. These findings suggest that the development of tauopathy is dependent on far more than just hyperphosphorylation. The biological and pathological processes involved in tau post-translational modifications and CSF tau production are largely unknown
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