Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau

Takahashi, Muneaki; Miyata, Haruka; Kametani, Fuyuki; Nonaka, Takashi; Akiyama, Haruhiko; Hisanaga, Shin‐ichi; Hasegawa, Masato

doi:10.1007/s00401-015-1415-2

Cited by 76 publications

(60 citation statements)

References 62 publications

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“…Remarkably, results of our immunocytochemical experiments provide novel evidence that APP expression is fundamental for tau uploading from astrocytes. Different mechanisms may underlie APPmediated tau internalization: i) APP may act as receptor for tau, as proposed for uptake of extracellular fibrils (Takahashi et al, 2015); or ii) it may affect HPSG expression (Cappai et al, 2005;Reinhard et al, 2013) that has been also demonstrated to be necessary for tau internalization in neurons (Holmes et al, 2013;Mirbaha et al, 2015).…”

Section: Do the Inhibitory Effects We Observed In Hippocampal Neuronsmentioning

confidence: 99%

Reduced gliotransmitter release from astrocytes mediates tau‐induced synaptic dysfunction in cultured hippocampal neurons

Piacentini

Puma

Mainardi

et al. 2017

Glia

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Tau is a microtubule-associated protein exerting several physiological functions in neurons. In Alzheimer's disease (AD) misfolded tau accumulates intraneuronally and leads to axonal degeneration. However, tau has also been found in the extracellular medium. Recent studies indicated that extracellular tau uploaded from neurons causes synaptic dysfunction and contributes to tau pathology propagation. Here we report novel evidence that extracellular tau oligomers are abundantly and rapidly accumulated in astrocytes where they disrupt intracellular Ca2+ signaling and Ca2+-dependent release of gliotransmitters, especially ATP. Consequently, synaptic vesicle release, the expression of pre- and post-synaptic proteins, and mEPSC frequency and amplitude were reduced in neighboring neurons. Notably, we found that tau uploading from astrocytes required the amyloid precursor protein, APP. Collectively, our findings suggests that astrocytes play a critical role in the synaptotoxic effects of tau via reduced gliotransmitter availability, and that astrocytes are major determinants of tau pathology in AD.

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Section: Do the Inhibitory Effects We Observed In Hippocampal Neuronsmentioning

confidence: 99%

Reduced gliotransmitter release from astrocytes mediates tau‐induced synaptic dysfunction in cultured hippocampal neurons

Piacentini

Puma

Mainardi

et al. 2017

Glia

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“…␣-Syn samples were analyzed by 12% SDS-PAGE with 2-mercaptoethanol and stained with CBB. Immunoblotting with polyclonal antibody syn131-140 (1:2000) directed against a synthetic peptide (residues 131-140) (41, 46) was performed as described previously (47). Gel images were recorded with a Gel Doc TM EZ Imager (Bio-Rad).…”

Section: Experimental Proceduersmentioning

confidence: 99%

The Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation

Tarutani

Suzuki

Shimozawa

et al. 2016

Journal of Biological Chemistry

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118

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Aggregates of abnormal proteins are widely observed in neuronal and glial cells of patients with various neurodegenerative diseases, and it has been proposed that prion-like behavior of these proteins can account for not only the onset but also the progression of these diseases. However, it is not yet clear which abnormal protein structures function most efficiently as seeds for prion-like propagation. In this study, we aimed to identify the most pathogenic species of ␣-synuclein (␣-syn), the main component of the Lewy bodies and Lewy neurites that are observed in ␣-synucleinopathies. We prepared various forms of ␣-syn protein and examined their seeding properties in vitro in cells and in mouse experimental models. We also characterized these ␣-syn species by means of electron microscopy and thioflavin fluorescence assays and found that fragmented ␤ sheetrich fibrous structures of ␣-syn with a length of 50 nm or less are the most efficient promoters of accumulation of phosphorylated ␣-syn, which is the hallmark of ␣-synucleinopathies. These results indicate that fragmented amyloid-like aggregates of short ␣-syn fibrils are the key pathogenic seeds that trigger prion-like conversion.

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“…in a scenario when aggregates enter the host cell from the extracellular environment (e.g. [32][33][34]), the proteasomal mechanisms that are involved in clearing cytosolic misfolded proteins to prevent intracellular aggregate formation may be distinct from its fibril-fragmenting function.…”

Section: Distinct Activities Of Proteasome Holoenzyme Prevent Tau Aggmentioning

confidence: 99%

Filamentous aggregates are fragmented by the proteasome holoenzyme

Cliffe

Sang

Kundel

et al. 2018

Preprint

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Filamentous aggregates (fibrils) are regarded as the final stage in the assembly of amyloidogenic proteins and are formed in many neurodegenerative diseases. Accumulation of aggregates occurs as a result of an imbalance between their formation and removal. Although there have been numerous studies of the aggregation process in vitro, far fewer studies of aggregate disassembly and degradation are available. Here we use single-aggregate imaging to show that large fibrils assembled from full-length tau are substrates of the 26S proteasome holoenzyme, which fragments them into small aggregates. TEM further revealed that these small aggregate species had no distinct structure. The intact proteasome holoenzyme is required to effectively target fibrils. Interestingly, while degradation of monomeric tau was not inhibited by ATPγS, fibril fragmentation was predominantly dependent on the ATPase activity of the proteasome. The proteasome holoenzyme was also found to target fibrils assembled from α -synuclein (αS), suggesting that its fibril fragmenting function may be a general mechanism. The fragmented species produced by the proteasome showed significant toxicity to human cell lines compared to intact fibrils. Together, our results indicate that the proteasome holoenzyme possesses a novel fragmentation function that disassembles large fibrils into smaller and more cytotoxic species. (196 words)

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Extracellular association of APP and tau fibrils induces intracellular aggregate formation of tau

Cited by 76 publications

References 62 publications

Reduced gliotransmitter release from astrocytes mediates tau‐induced synaptic dysfunction in cultured hippocampal neurons

Reduced gliotransmitter release from astrocytes mediates tau‐induced synaptic dysfunction in cultured hippocampal neurons

The Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation

Filamentous aggregates are fragmented by the proteasome holoenzyme

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