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...

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Autores: del Ser-Badia, A, Soto-Faguás, CM, Vecino, R, Vendrell, C, Molina-Porcel, L, Sánchez-Valle, R, Rodríguez-Alvarez, J, Vicario, C, Saura, CA
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2026
País:España
Recursos:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositório:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:dnet:r-i3pt______::97ee246b1635a1c380619f947361011e
Acesso em linha:https://i3pt.portalinvestigacion.com/publicaciones/7178
Access Level:Acceso aberto
Palavra-chave:Alzheimer's disease
Autophagy
Proteasome
gamma-Secretase
Neurodegeneration
Proteostasis
Tauopathies
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spelling Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathwaysdel Ser-Badia, ASoto-Faguás, CMVecino, RVendrell, CMolina-Porcel, LSánchez-Valle, RRodríguez-Alvarez, JVicario, CSaura, CAAlzheimer's diseaseAutophagyProteasomegamma-SecretaseNeurodegenerationProteostasisTauopathiesMutations 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.BMC2026info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://i3pt.portalinvestigacion.com/publicaciones/7178Acta Neuropathologica CommunicationsISSN: 20515960reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulíinstname:Institut d'Investigació i Innovació Parc Taulí (I3PT)Inglésinfo:eu-repo/semantics/openAccessoai:dnet:r-i3pt______::97ee246b1635a1c380619f947361011e2026-06-21T15:30:37Z
dc.title.none.fl_str_mv Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
title Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
spellingShingle Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
del Ser-Badia, A
Alzheimer's disease
Autophagy
Proteasome
gamma-Secretase
Neurodegeneration
Proteostasis
Tauopathies
title_short Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
title_full Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
title_fullStr Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
title_full_unstemmed Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
title_sort Presenilin-dependent regulation of neuronal tau pathology via the autophagy and proteasome pathways
dc.creator.none.fl_str_mv del Ser-Badia, A
Soto-Faguás, CM
Vecino, R
Vendrell, C
Molina-Porcel, L
Sánchez-Valle, R
Rodríguez-Alvarez, J
Vicario, C
Saura, CA
author del Ser-Badia, A
author_facet del Ser-Badia, A
Soto-Faguás, CM
Vecino, R
Vendrell, C
Molina-Porcel, L
Sánchez-Valle, R
Rodríguez-Alvarez, J
Vicario, C
Saura, CA
author_role author
author2 Soto-Faguás, CM
Vecino, R
Vendrell, C
Molina-Porcel, L
Sánchez-Valle, R
Rodríguez-Alvarez, J
Vicario, C
Saura, CA
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer's disease
Autophagy
Proteasome
gamma-Secretase
Neurodegeneration
Proteostasis
Tauopathies
topic Alzheimer's disease
Autophagy
Proteasome
gamma-Secretase
Neurodegeneration
Proteostasis
Tauopathies
description 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.
publishDate 2026
dc.date.none.fl_str_mv 2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://i3pt.portalinvestigacion.com/publicaciones/7178
url https://i3pt.portalinvestigacion.com/publicaciones/7178
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv Acta Neuropathologica Communications
ISSN: 20515960
reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
instname:Institut d'Investigació i Innovació Parc Taulí (I3PT)
instname_str Institut d'Investigació i Innovació Parc Taulí (I3PT)
reponame_str r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
collection r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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