Severe neurodegeneration in brains of transgenic rats producing human tau prions.
Hyperphosphorylation
MAPT
Misfolding
Prions
Tauopathy
Transgenic rat
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
20 Aug 2024
20 Aug 2024
Historique:
received:
09
04
2024
accepted:
16
07
2024
revised:
16
07
2024
medline:
20
8
2024
pubmed:
20
8
2024
entrez:
19
8
2024
Statut:
epublish
Résumé
Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion-mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer's disease and other tau prion disorders.
Identifiants
pubmed: 39160375
doi: 10.1007/s00401-024-02771-5
pii: 10.1007/s00401-024-02771-5
doi:
Substances chimiques
tau Proteins
0
Prions
0
MAPT protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
25Subventions
Organisme : NIH HHS
ID : P01AG002132
Pays : United States
Organisme : Henry M. Jackson Foundation
ID : HU0001-21-2-065, subaward 5802
Organisme : Rainwater Charitable Foundation
ID : A130576
Organisme : CurePSP
ID : A126423
Organisme : Brockman Foundation
ID : A131948
Organisme : Sherman Fairchild Foundation
ID : A131057
Informations de copyright
© 2024. The Author(s).
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