Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila

Catterson, James H.; Minkley, Lucy; Aspe, Salomé; Judd-Mole, Sebastian; Moura, Sofia; Dyson, Miranda C.; Rajasingam, Arjunan; Woodling, Nathaniel S.; Atilano, Magda L.; Ahmad, Mumtaz; Durrant, Claire S.; Spires-Jones, Tara L.; Partridge, Linda

doi:10.1016/j.neurobiolaging.2023.09.008

Cited by 3 publications

(1 citation statement)

References 96 publications

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“…The following stocks were obtained from the Bloomington Drosophila Stock Center: PDF-GAL4 (#6900, now #80939), Orco-GAL4 (#26818), GH146-QF, QUAS-mCD8:RFP (#30037), UAS-mCD8:GFP (#5137), UAS-mCD8:RFP (#27392), UAS-myr:GFP, QUAS-mtdTom:HA, trans-Tango (#77124), QUAS-Aβ 40 (#83346), QUAS-Aβ 42 (#83346), UAS-hTau WT(0N4R) (#78847), UAS-hTau WT(2N4R) (#78861). The control w Dah was a kind gift from Dr Linda Partridge (UCL, UK) 41 . UAS-hTau P301L(2N4R) was a kind gift from Dr Bess Frost (UT Health San Antonio, USA) 42 .…”

Section: Methodsmentioning

confidence: 99%

Drosophilaappear resistant to trans-synaptic tau propagation

Catterson,

Mouofo,

Soler

et al. 2024

Preprint

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Alzheimers disease (AD) is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of AD is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models and indirect evidence for tau spread via synapses has been observed in human AD. Halting tau propagation is a promising therapeutic target for AD, thus a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau (hTau) in Drosophila melanogaster. Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing 4 different human tau constructs in two distinct neuronal populations reveal a robust resistance in Drosophila to the trans-synaptic spread of hTau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global hTau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that Drosophila expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in Drosophila may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.

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Section: Methodsmentioning

confidence: 99%

Drosophilaappear resistant to trans-synaptic tau propagation

Catterson,

Mouofo,

Soler

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Drosophila appear resistant to trans-synaptic tau propagation

Catterson,

Mouofo,

López De Toledo Soler

et al. 2024

Brain Communications

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Alzheimer’s disease is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of Alzheimer’s disease is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models, and indirect evidence for tau spread via synapses has been observed in human Alzheimer’s disease. Halting tau propagation is a promising therapeutic target for Alzheimer’s disease; thus, a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau in Drosophila melanogaster. Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing four different human tau constructs in two distinct neuronal populations reveals a robust resistance in Drosophila to the trans-synaptic spread of human tau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global human tau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that Drosophila expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in Drosophila may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.

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Systemic comparison of molecular characteristics in different skin fibroblast senescent models

Fang,

Zhang,

et al. 2024

Chinese Medical Journal

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Background: Senescent human skin primary fibroblast (FB) models have been established for studying aging-related, proliferative, and inflammatory skin diseases. The aim of this study was to compare the transcriptome characteristics of human primary dermal FBs from children and the elderly with four senescence models. Methods: Human skin primary FBs were obtained from healthy children (FB-C) and elderly donors (FB-E). Senescence models were generated by ultraviolet B irradiation (FB-UVB), D-galactose stimulation (FB-D-gal), atazanavir treatment (FB-ATV), and replication exhaustion induction (FB-P30). Flow cytometry, immunofluorescence staining, real-time quantitative polymerase chain reaction, co-culturing with immune cells, and bulk RNA sequencing were used for systematic comparisons of the models. Results: In comparison with FB-C, FB-E showed elevated expression of senescence-related genes related to the skin barrier and extracellular matrix, proinflammatory factors, chemokines, oxidative stress, and complement factors. In comparison with FB-E, FB-UVB and FB-ATV showed higher levels of senescence and expression of the genes related to the senescence-associated secretory phenotype (SASP), and their shaped immune microenvironment highly facilitated the activation of downstream immune cells, including T cells, macrophages, and natural killer cells. FB-P30 was most similar to FB-E in terms of general transcriptome features, such as FB migration and proliferation, and aging-related characteristics. FB-D-gal showed the lowest expression levels of senescence-related genes. In comparisons with the single-cell RNA sequencing results, FB-E showed almost complete simulation of the transcriptional spectrum of FBs in elderly patients with atopic dermatitis, followed by FB-P30 and FB-UVB. FB-E and FB-P30 showed higher similarity with the FBs in keloids. Conclusions: Each senescent FB model exhibited different characteristics. In addition to showing upregulated expression of natural senescence features, FB-UVB and FB-ATV showed high expression levels of senescence-related genes, including those involved in the SASP, and FB-P30 showed the greatest similarity with FB-E. However, D-galactose-stimulated FBs did not clearly present aging characteristics.

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Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila

Cited by 3 publications

References 96 publications

Drosophilaappear resistant to trans-synaptic tau propagation

Drosophilaappear resistant to trans-synaptic tau propagation

Drosophila appear resistant to trans-synaptic tau propagation

Systemic comparison of molecular characteristics in different skin fibroblast senescent models

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