BACKGROUND: Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the toxic protein accumulation. In a subset of frontotemporal dementia (FTD) cases, mutations in the microtubule-associated protein tau (MAPT) that alter the relative levels of specific tau isoforms are sufficient to cause tau inclusions in neurons and astroglia and neurodegeneration without the presence of mutated protein (e.g. MAPTIVS10+16). However, the pathogenic events triggered by the expression of the alternatively spliced tau remain poorly understood. METHOD: To determine whether altered tau splicing induced from MAPT IVS10+16 mutations is sufficient to alter proteostasis in neurons and glia, we used human induced pluripotent stem cell (iPSC)-derived neurons and astrocytes from patients carrying the MAPT IVS10+16 mutation and CRISPR/Cas9, isogenic corrected controls. RESULT: We found that neurons from MAPT IVS10+16 carriers exhibited significantly higher levels of 4 repeat tau, deficits in lysosomal trafficking, and reduced lysosomal acidity relative to isogenic-control neurons. Additionally, MAPTIVS10+16 was sufficient to reduce genes associated with lysosomal biogenesis (regulated by TFEB). Interestingly, mutant astrocytes also produce elevated 4 repeat tau levels and exhibit several key hallmarks of cellular aging. Mutant astrocytes were larger in size with enlarged nuclei compared to isogenic controls. In addition to this hypertrophy phenotype, mutant astrocytes exhibited significantly elevated levels of senescence genes. Furthermore, markers of proteostasis were altered in mutant astrocytes: MAPT IVS10+16 carriers exhibited an increase in acidic lysosomes compared to isogenic-control astrocytes, and TFEB-regulated genes were upregulated MAPT IVS10+16 astrocytes. CONCLUSION: Our findings suggest that altered tau splicing induced by the MAPT IVS10+16 mutation is sufficient to cause aging signatures, including hypertrophy, senescence, and altered proteostasis in a cell-type specific manner.
|Journal||Alzheimer's & dementia : the journal of the Alzheimer's Association|
|State||Published - Dec 1 2021|