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Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.

ABSTRACT: Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid beta (Abeta) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (DeltaTau) by executioner caspases. Following caspase-cleavage, DeltaTau facilitates nucleation-dependent filament formation and readily adopts a conformational change recognized by the early pathological tau marker MC1. DeltaTau can be phosphorylated by glycogen synthase kinase-3beta and subsequently recognized by the NFT antibody PHF-1. In transgenic mice and AD brains, DeltaTau associates with both early and late markers of NFTs and is correlated with cognitive decline. Additionally, DeltaTau colocalizes with Abeta(1-42) and is induced by Abeta(1-42) in vitro. Collectively, our data imply that Abeta accumulation triggers caspase activation, leading to caspase-cleavage of tau, and that this is an early event that may precede hyperphosphorylation in the evolution of AD tangle pathology. These results suggest that therapeutics aimed at inhibiting tau caspase-cleavage may prove beneficial not only in preventing NFT formation, but also in slowing cognitive decline.

SUBMITTER: Rissman RA

PROVIDER: S-EPMC437967 | biostudies-literature | 2004 Jul

REPOSITORIES: biostudies-literature

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Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.

Rissman Robert A RA Poon Wayne W WW Blurton-Jones Mathew M Oddo Salvatore S Torp Reidun R Vitek Michael P MP LaFerla Frank M FM Rohn Troy T TT Cotman Carl W CW

The Journal of clinical investigation 20040701 1

Neurofibrillary tangles (NFTs) are composed of abnormal aggregates of the cytoskeletal protein tau. Together with amyloid beta (Abeta) plaques and neuronal and synaptic loss, NFTs constitute the primary pathological hallmarks of Alzheimer disease (AD). Recent evidence also suggests that caspases are activated early in the progression of AD and may play a role in neuronal loss and NFT pathology. Here we demonstrate that tau is cleaved at D421 (DeltaTau) by executioner caspases. Following caspase- ...[more]

PMID: 15232619

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Project description:Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer's disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically ending at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-224, and x-224 tau. Immunoassays were applied to soluble brain fractions from pathologically confirmed subjects (81 AD patients, 33 controls), CSF from three cross-sectional and two longitudinal cohorts (a total of 133 AD, 38 MCI, 20 MCI-AD, 31 PSP, 15 CBS patients, and 91 controls), and neuronally- and peripherally-derived extracellular vesicles (NDEVs and PDEVs, respectively) in serum from four AD patients and four controls. Anti-tau 224 antibody stained neurofibrillary tangles and neuropil threads, while anti-tau 123 only showed weak cytoplasmic staining in AD. N-224 tau was lower in the AD soluble brain fraction compared to controls, while N-123 tau showed similar levels. N-224 tau was higher in AD compared to controls in all CSF cohorts (p < 0.001), but not N-123 tau. Decrease in cognitive performance and conversion from MCI to AD were associated with increased baseline CSF levels of N-224 tau (p < 0.0001). N-224 tau concentrations in PSP and CBS were significantly lower than in AD (p < 0.0001) and did not correlate to t-tau and p-tau. In a longitudinal cohort, CSF N-224 tau levels were stable over 6 months, with no significant effect of treatment with AChE inhibitors. N-224 tau was present in NDEVs, while N-123 tau showed comparable concentrations in both vesicle types. We suggest that N-123 tau is produced both in CNS and PNS and represents a general marker of tau metabolism, while N-224 tau is neuron-specific, present in the tangles, secreted in CSF, and upregulated in AD, suggesting a link between tau cleavage and propagation, tangle pathology, and cognitive decline.

Project description:ImportanceIn Alzheimer disease (AD), tau filaments form neuronal inclusions in neurites (neuropil threads) and in somata (neurofibrillary tangles), and neurite tau pathology constitutes the most common pathology. Positron emission tomography (PET) ligands have been developed to detect in vivo tau pathology in AD. However, the association of AD tau pathology post mortem with in vivo tau PET retention has not been established. Therefore, there is a need to investigate the associations of tau PET with postmortem tau pathology in AD.ObjectiveTo study the association of regional in vivo retention of the tau PET ligand [18F]flortaucipir (previously known as AV1451) with the density of tau neuropathology in the corresponding brain regions in a patient with AD.Design, setting, and participantsThe patient was a man in his 40s with AD caused by a PSEN1 mutation. Between May 2015 and December 2016, he underwent 2 [18F]flortaucipir PET scans at Lund University Hospital, Lund, Sweden. Postmortem analysis was performed 12 months after the last PET scan. Tau pathology was assessed using phosphorylated tau (AT8) immunohistochemistry and Gallyas silver staining. In addition to the regional total tau pathology burden, the density of tau-positive neurites and intrasomal tau tangles were quantified using a stereology-based method. Further, β-amyloid-containing plaques were detected using 4G8 immunohistochemistry. Data were analyzed between January 2018 and August 2018.Main outcomes and measuresRegional standardized uptake value ratios of [18F]flortaucipir were compared with the amount of tau pathology in the corresponding brain areas.ResultsIn this patient, the clinical disease symptoms progressed rapidly in life, paralleled with an annual increase of tau PET retention of 20% to 40% in many cortical regions. Compared with postmortem immunohistochemistry, regional in vivo uptake of [18F]flortaucipir was correlated with the density of tau-positive neurites (AT8: rs = 0.87; P < .001; Gallyas: rs = 0.92; P < .001), intrasomal tau tangles (AT8: rs = 0.65; P = .01; Gallyas: rs = 0.84; P < .001), and total tau burden (AT8: rs = 0.84; P < .001; Gallyas: rs = 0.82; P < .001). No correlations between [18F]flortaucipir and β-amyloid pathology were found.Conclusions and relevanceThese results indicate that [18F]flortaucipir PET retention is a robust in vivo measure of the total AD tau burden.

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Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.

Publications

Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology.

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