| Autor: |
Mahali, Sidhartha, Martinez, Rita, Hu, Miwei, Marsh, Jacob, Temple, Sally, Karch, Celeste M. |
| Zdroj: |
Alzheimer's & Dementia: The Journal of the Alzheimer's Association; Dec2021 Supplement S3, Vol. 17 Issue 3, p1-1, 1p |
| Abstrakt: |
Background: Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the toxic accumulation of protein. In a subset of frontotemporal dementia (FTD) cases, mutations in the microtubule‐associated protein tau (MAPT) that alter the relative levels of 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 tau containing 4 microtubule binding repeats (4R tau), deficits in lysosomal trafficking, and acidity relative to isogenic‐control neurons. Conversely, astrocytes from MAPT IVS10+16 carriers exhibited morphologically an increase in acidic lysosomes compared to isogenic‐control astrocytes. Astrocytes from MAPT IVS10+16 carriers were also larger in size, consistent with cellular hypertrophy observed in brains from FTD‐tau patients. Conclusion: Our findings suggest that altered tau splicing induced by the MAPT IVS10+16 mutation is sufficient to cause impaired lysosomal function and altered proteostasis in a cell‐type specific manner. [ABSTRACT FROM AUTHOR] |
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