期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2204179119
关键词
Tau; intron retention; Alzheimer disease
资金
- Temasek Core Funding [3160, BA40]
- Brains for Dementia Research network
The retention of intron 11 of the Tau gene in Alzheimer's disease (AD) leads to the production of truncated Tau11i protein, which is enriched in the brains of AD patients and exhibits biochemical properties resembling pathological Tau species. Therefore, the retention of intron 11 of the Tau gene might be an early biomarker of AD pathology.
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta plaques and Tau tangles in brain tissues. Recent studies indicate that aberrant splicing and increased level of intron retention is linked to AD pathogenesis. Bioinformatic analysis revealed increased retention of intron 11 at the Tau gene in AD female dorsal lateral prefrontal cortex as compared to healthy controls, an observation validated by quantitative polymerase chain reaction using different brain tissues. Retention of intron 11 introduces a premature stop codon, resulting in the production of truncated Tau11i protein. Probing with customized antibodies designed against amino acids encoded by intron 11 showed that Tau11i protein is more enriched in AD hippocampus, amygdala, parietal, temporal, and frontal lobe than in healthy controls. This indicates that Tau messenger RNA with the retained intron is translated in vivo instead of being subjected to nonsense-mediated decay. Compared to full-length Tau441 isoform, ectopically expressed Tau11i forms higher molecular weight species, is enriched in Sarkosy-linsoluble fraction, and exhibits greater protein stability in cycloheximide assay. Stably expressed Tau11i also shows weaker colocalization with a-tubulin of microtubule network in human mature cortical neurons as compared to Tau441. Endogenous Tau11i is enriched in Sarkosyl-insoluble fraction in AD hippocampus and forms aggregates that colocalize weakly with Tau4R fibril-like structure in AD temporal lobe. The elevated level of Tau11i protein in AD brain tissues tested, coupled with biochemical properties resembling pathological Tau species suggest that retention of intron 11 of Tau gene might be an early biomarker of AD pathology.
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