In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 4 ( 2023-4-4), p. e0283941-
Abstract:
Intracellular accumulation of tau protein is a hallmark of Alzheimer’s Disease and Progressive Supranuclear Palsy, as well as other neurodegenerative disorders collectively known as tauopathies. Despite our increasing understanding of the mechanisms leading to the initiation and progression of tau pathology, the field still lacks appropriate disease models to facilitate drug discovery. Here, we established a novel and modulatable seeding-based neuronal model of full-length 4R tau accumulation using humanized mouse cortical neurons and seeds from P301S human tau transgenic animals. The model shows specific and consistent formation of intraneuronal insoluble full-length 4R tau inclusions, which are positive for known markers of tau pathology (AT8, PHF-1, MC-1), and creates seeding competent tau. The formation of new inclusions can be prevented by treatment with tau siRNA, providing a robust internal control for use in qualifying the assessment of potential therapeutic candidates aimed at reducing the intracellular pool of tau. In addition, the experimental set up and data analysis techniques used provide consistent results in larger-scale designs that required multiple rounds of independent experiments, making this is a versatile and valuable cellular model for fundamental and early pre-clinical research of tau-targeted therapies.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0283941
DOI:
10.1371/journal.pone.0283941.g001
DOI:
10.1371/journal.pone.0283941.g002
DOI:
10.1371/journal.pone.0283941.g003
DOI:
10.1371/journal.pone.0283941.g004
DOI:
10.1371/journal.pone.0283941.g005
DOI:
10.1371/journal.pone.0283941.g006
DOI:
10.1371/journal.pone.0283941.g007
DOI:
10.1371/journal.pone.0283941.t001
DOI:
10.1371/journal.pone.0283941.t002
DOI:
10.1371/journal.pone.0283941.s001
DOI:
10.1371/journal.pone.0283941.s002
DOI:
10.1371/journal.pone.0283941.s003
DOI:
10.1371/journal.pone.0283941.s004
DOI:
10.1371/journal.pone.0283941.s005
DOI:
10.1371/journal.pone.0283941.s006
DOI:
10.1371/journal.pone.0283941.s007
DOI:
10.1371/journal.pone.0283941.s008
DOI:
10.1371/journal.pone.0283941.s009
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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