Calpain-mediated tau fragmentation is altered in Alzheimer’s disease progression

Chen, Hsu-Hsin; Liu, Peter; Auger, Paul; Lee, Seung-Hye; Adolfsson, Oskar; Rey-Bellet, Lorianne; Lafrance‐Vanasse, Julien; Friedman, Brad A.; Pihlgren, Maria; Muhs, Andreas; Pfeifer, Andrea; Ernst, James A.; Ayalon, Gai; Wildsmith, Kristin R.; Beach, Thomas G.; Brug, Marcel P. van der

doi:10.1038/s41598-018-35130-y

Cited by 41 publications

(40 citation statements)

References 63 publications

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“…Tau proteins, mutant and wild-type, in human brain are heterogeneous in molecular forms with respect to different repeat domains and proteolytic fragments (1,(127)(128)(129)(130)(131)(132). The finding in this study that the P301L and V337M Tau mutations result in dysregulation of exosome protein cargo leads the question of what are the effects of other Tau isoforms on exosome cargoes and pathogenicity?…”

Section: Molecular and Cellular Proteomics 196 1027mentioning

confidence: 79%

Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

Podvin

Jones

Liu

et al. 2020

Molecular & Cellular Proteomics

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Accumulation and propagation of hyperphosphorylated Tau (p-Tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating Tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-Tau pathology after injection into mouse brain. To gain an understanding of the mTau exosome cargo involved in Tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in 1) proteins uniquely present only in mTau, and not control exosomes, 2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and 3) shared proteins which were significantly upregulated or downregulated in mTau compared with control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-Tau. Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes. Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or downregulation of protein cargo to result in pathogenic mTau exosomes capable of in vivo propagation of p-Tau neuropathology in mouse brain.

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Section: Molecular and Cellular Proteomics 196 1027mentioning

confidence: 79%

Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

Podvin

Jones

Liu

et al. 2020

Molecular & Cellular Proteomics

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“…In this study, we found that reduced tau phosphorylation makes tau more susceptible to calpain cleavage to generate 35-kDa N-terminal fragments. The calpain cleavage site of tau has been reported to be near or inside the MTBD (Chen et al., 2018, Garg et al., 2011). Therefore, the resultant tau fragment either may have lost its ability to stabilize microtubules or have gained a toxic function to destabilize them, ultimately triggering the axonal phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs

et al. 2019

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SummaryMutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer’s disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention.

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“…Calpain-1 and 2 are abundantly expressed in the CNS [201]. Calpain-1 cleaves tau at Lys44, Arg230, Arg242, Gly323, and Gly326, while calpain-2 cleaves tau at Arg230 [202][203][204][205][206]. Calpain-mediated tau cleavage generates several truncated tau isoforms, including 17 kDa tau45-230, and 24 kDa tau243-441 products [204,207].…”

Section: Truncationmentioning

confidence: 99%

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

Guo

Zhang

Zeng

et al. 2020

Mol Neurodegeneration

509

365

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Alzheimer's disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. There is currently no effective treatment for AD, which may be attributed in part to lack of a clear underlying mechanism. Studies within the last few decades provide growing evidence for a central role of amyloid β (Aβ) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. Herein, we review recent progress with respect to Aβ-and tau-associated mechanisms, and discuss glial dysfunction in AD with emphasis on neuronal and glial receptors that mediate Aβ-induced toxicity. We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. Although we have gained much towards understanding various aspects underlying this devastating neurodegenerative disorder, greater commitment towards research in molecular mechanism, diagnostics and treatment will be needed in future AD research.

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Calpain-mediated tau fragmentation is altered in Alzheimer’s disease progression

Cited by 41 publications

References 63 publications

Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses

Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

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