The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

Carlomagno, Yari; Manne, Sireesha; DeTure, Michael; Prudencio, Mercedes; Zhang, Yong Jie; Al-Shaikh, Rana Hanna; Dunmore, Judith A.; Daughrity, Lillian M.; Song, Yuping; Castanedes‐Casey, Monica; Lewis‐Tuffin, Laura J.; Nicholson, Katharine; Wszołek, Zbigniew K.; Dickson, Dennis W.; Fitzpatrick, Anthony; Petrucelli, Leonard; Cook, Casey

doi:10.1016/j.celrep.2021.108843

Cited by 36 publications

(21 citation statements)

References 55 publications

(86 reference statements)

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“…To obtain a sufficient yield of tau filaments from PSP tissue, we evaluated the amount of tau present within the sarkosyl-insoluble (P3) fraction from four different brain regions in three different PSP cases, without pronase-treatment to preserve posttranslational modifications (Arakhamia et al, 2020;Carlomagno et al, 2021). As tau levels were consistently highest in the P3 fractions from caudate and frontal cortex, we screened these two regions in an additional 12 PSP cases.…”

Section: Psp Casementioning

confidence: 99%

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Chang

Xiang

Wang

et al. 2022

Cell

Self Cite

109

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Section: Psp Casementioning

confidence: 99%

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Chang

Xiang

Wang

et al. 2022

Cell

Self Cite

109

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“…The same was true of K11 and K12 constructs (tau residues 244–394 for K11, and the same sequences, excluding R2, for K12) ( Wille et al, 1992 ). Moreover, proteins comprising the ordered cores of tau filaments from AD [residues 306–378], PiD [residues 254–378, but excluding R2], and CBD [residues 274–380] have been reported to assemble into filaments ( Carlomagno et al, 2021 ). It remains to be established if the structures of these filaments resembled those from diseased brain.…”

Section: Introductionmentioning

confidence: 99%

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

Lövestam

Koh

Knippenberg

et al. 2022

eLife

150

166

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Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

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“…In addition to being involved in the assembly of the cytoskeleton, Tau can also bind to other proteins and play a role in cell signaling through phosphorylation. When the phosphorylated regulatory system of Tau is disrupted, such as by hyperphosphorylation, neurological symptoms such as cognitive decline can emerge ( Gratuze et al, 2018 ; Li et al, 2019 ; Carlomagno et al, 2021 ). Numerous studies have shown that neuronal tangle formed by hyperphosphorylated polymerization of Tau protein is another hallmark pathological feature of AD in addition to Aβ deposition ( Hanger et al, 2007 ; Reynolds et al, 2008 ).…”

Section: Phosphatidylinositol-specific Phospholipase C Gamma 2 Acts A...mentioning

confidence: 99%

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

Ran

Wang

et al. 2022

Front. Cell Dev. Biol.

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Alzheimer’s disease (AD) is an irreversible neurodegenerative disease mainly characterized by memory loss and cognitive decline. The etiology of AD is complex and remains incompletely understood. In recent years, genome-wide association studies (GWAS) have increasingly highlighted the central role of microglia in AD pathology. As a trans-membrane receptor specifically present on the microglia in the central nervous system, phosphatidylinositol-specific phospholipase C gamma 2 (PLCγ2) plays an important role in neuroinflammation. GWAS data and corresponding pathological research have explored the effects of PLCG2 variants on amyloid burden and tau pathologies that underline AD. The link between PLCγ2 and other AD-related effectors in human and mouse microglia has also been established, placing PLCγ2 downstream of the triggering receptor expressed on myeloid cells 2 (TREM2), toll-like receptor 4 (TLR4), Bruton’s tyrosine kinase (BTK), and colony-stimulating factor 1 receptor (CSF1R). Because the research on PLCγ2’s role in AD is still in its early stages, few articles have been published, therefore in this paper, we integrate the relevant research published to date, review the structural features, expression patterns, and related pathways of PLCγ2, and summarize the recent studies on important PLCG2 variants related to AD. Furthermore, the possibility and challenge of using PLCγ2 to develop therapeutic drugs for AD are also discussed.

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The AD tau core spontaneously self-assembles and recruits full-length tau to filaments

Cited by 36 publications

References 55 publications

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy

PLCγ2 impacts microglia-related effectors revealing variants and pathways important in Alzheimer’s disease

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