The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction
| dc.contributor.author | Buchholz, Sarah | |
| dc.contributor.author | Kabbani, Mohamed Aghyad Al | |
| dc.contributor.author | Bell-Simons, Michael | |
| dc.contributor.author | Kluge, Lena | |
| dc.contributor.author | Cagmak, Cagla | |
| dc.contributor.author | Klimek, Jennifer | |
| dc.contributor.author | Haag, Natja | |
| dc.contributor.author | Carvalho, Lukas Iohan da Cruz | |
| dc.contributor.author | Coulon, Audrey | |
| dc.contributor.author | Costa, Marcos Romualdo | |
| dc.contributor.author | Kilinc, Devrim | |
| dc.contributor.author | Zempel, Hans | |
| dc.contributor.authorID | https://orcid.org/0000-0001-9426-4610 | |
| dc.date.accessioned | 2026-01-14T17:49:13Z | |
| dc.date.available | 2026-01-14T17:49:13Z | |
| dc.date.issued | 2025 | |
| dc.description.resumo | Introduction: Human tau protein, composed of six brain-specific isoforms, is a major driver of Alzheimer's disease (AD). The role of its isoforms however remains unclear and human AD models are scarce. Methods: We generated human MAPT- (tau-) knockout (KO) induced pluripotent stem cells (iPSC) using CRISPR/Cas9, differentiated these into glutamatergic neurons, and assessed isoform-specific functions of tau in these neurons. We used omic- approaches, live-cell imaging, subcompartmental analysis, and lentivirus-based reintroduction of specific tau isoforms to investigate isoform-mediated neuronal dysfunction in an AD model. Results: Tau KO human iPSC-derived neurons showed decreased neurite outgrowth and axon initial segment length and, notably, resisted amyloid beta oligomer (AβO)-induced neuronal activity reduction. Introducing the 1N4R-tau isoform, but not other isoforms, confers AβO vulnerability and increases KxGS phosphorylation of tau, without altering neuronal activity or microtubule modifications. Discussion: While tau KO impacts neuronal development and activity, tau-KO also confers resistance against AβO insult. 1N4R-tau likely mediates AβO-induced and phosphorylated tau toxicity, representing a novel prime therapeutic target for AD | |
| dc.identifier.citation | BUCHHOLZ, Sarah; KABBANI, Mohamed Aghyad Al; BELL‐SIMONS, Michael; KLUGE, Lena; CAGMAK, Cagla; KLIMEK, Jennifer; HAAG, Natja; IOHAN, Lukas C.; COULON, Audrey; COSTA, Marcos R.; KILINC, Devrim; ZEMPEL, HANS. The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC‐derived neurons to amyloid beta and phosphorylated tau‐induced neuronal dysfunction. Alzheimer'S & Dementia, [S. l.], v. 21, n. 5, p. e14403, fev. 2025. Doi: http://dx.doi.org/10.1002/alz.14403. Disponível em: https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/alz.14403. Acesso em: 13 jan. 2026 | |
| dc.identifier.doi | 10.1002/alz.14403 | |
| dc.identifier.uri | https://repositorio.ufrn.br/handle/123456789/67694 | |
| dc.language.iso | en | |
| dc.publisher | Alzheimer’s Dement | |
| dc.rights | Attribution-NonCommercial-NoDerivs 3.0 Brazil | en |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/br/ | |
| dc.subject | Alzheimer's disease | |
| dc.subject | Amyloid beta | |
| dc.subject | Axon initial segment | |
| dc.subject | Human induced pluripotent stem cells | |
| dc.subject | Induced neurons | |
| dc.subject | Isoforms | |
| dc.subject | Knockout | |
| dc.subject | Neuronal activity | |
| dc.subject | Tau | |
| dc.subject | Tauopathy | |
| dc.title | The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction | |
| dc.type | article |