Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
Mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer's disease (AD) by enhancing cerebral accumulation of amyloid-beta (A beta) peptides and microtubule-associated protein tau (MAPT). How PS mutations affect A beta generation is well characterized, but the precise ce...
| Autores: | , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Institut d'Investigació i Innovació Parc Taulí (I3PT) |
| Repositorio: | r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí |
| OAI Identifier: | oai:dnet:r-i3pt______::97ee246b1635a1c380619f947361011e |
| Acceso en línea: | https://i3pt.portalinvestigacion.com/publicaciones/7178 |
| Access Level: | acceso abierto |
| Palabra clave: | Alzheimer's disease Autophagy Proteasome gamma-Secretase Neurodegeneration Proteostasis Tauopathies |
| Sumario: | Mutations in the presenilin (PS/PSEN) genes cause early-onset familial Alzheimer's disease (AD) by enhancing cerebral accumulation of amyloid-beta (A beta) peptides and microtubule-associated protein tau (MAPT). How PS mutations affect A beta generation is well characterized, but the precise cellular mechanisms by which PS dysfunction drives neuronal tau pathology are not fully understood. Here, we investigated the mechanisms linking PS/gamma-secretase-dependent tau pathology and autophagy/proteasome by employing pathological, imaging and molecular approaches in human brains, fibroblasts and induced pluripotent stem cells (iPSC)-derived neurons from PSEN1-linked familial AD carriers, and in a novel neuronal PS-deficient tauopathy transgenic mouse. We found enhanced levels and colocalization of pathological phosphorylated tau (pTau) and ubiquitin factor p62 in the hippocampus of dementia patients with familial AD-linked PSEN1 mutations, corticobasal degeneration and Pick's disease, suggesting disrupted proteasomal degradation in tauopathies. Human primary fibroblasts from PSEN1 G206D and/or L286P carriers showed elevated LC3-I and autolysosomes indicating autophagy flux alterations. Human iPSC-derived neurons harboring the familial-AD linked PSEN1 G206D mutation showed increased aggregated tau and reduced secreted tau, whereas pharmacological proteasome inhibition reduced significantly total and pTau (Ser396/404) while increasing its release. Consistently, proteasomal inhibition decreased intracellular tau and pTau and promoted tau release in human tau-expressing neurons through a mechanism that partially depends on PS. In the hippocampus of neuronal PS-deficient mice, Akt activation and GSK3 beta inhibition were associated with elevated levels of phosphorylated and aggregated tau and the ubiquitin-binding protein p62. In conclusion, PS function is required for autophagy/proteasome-mediated tau elimination in neurons, whereas that FAD-linked PSEN1 mutations cause progressive tau pathology by disrupting the proteasome and autophagy/lysosomal pathways. |
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