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Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

ABSTRACT: Hyperphosphorylated and truncated tau variants are enriched in neuropathological aggregates in diseases known as tauopathies. However, whether the interaction of these posttranslational modifications affects tau toxicity as a whole remains unresolved. By expressing human tau with disease-related Ser/Thr residues to simulate hyperphosphorylation, we show that despite severe neurodegeneration in full-length tau, with the truncation at Asp421, the toxicity is ameliorated. Cytological and biochemical analyses reveal that hyperphosphorylated full-length tau distributes in the soma, the axon, and the axonal terminal without evident distinction, whereas the Asp421-truncated version is mostly restricted from the axonal terminal. This discrepancy is correlated with the fact that fly expressing hyperphosphorylated full-length tau, but not Asp421-cleaved one, develops axonopathy lesions, including axonal spheroids and aberrant actin accumulations. The reduced presence of hyperphosphorylated tau in the axonal terminal is corroborated with the observation that flies expressing Asp421-truncated variants showed less motor deficit, suggesting synaptic function is preserved. The Asp421 cleavage of tau is a proteolytic product commonly found in the neurofibrillary tangles. Our finding suggests the coordination of different posttranslational modifications on tau may have an unexpected impact on the protein subcellular localization and cytotoxicity, which may be valuable when considering tau for therapeutic purposes.

SUBMITTER: Chi H

PROVIDER: S-EPMC7417559 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Accumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6-18 and 77E9 against tau 184-195 on tau and amyloid-? (A?) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.We immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 ?g of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and A? pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.We found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing A?40 and A?42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding A? plaques.These findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6-18 as a disease-modifying approach to AD and related tauopathies.

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Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model

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