Universität zu Köln

Buchholz, Sarah ORCID: 0000-0002-3636-1364, Kabbani, Mohamed Aghyad Al ORCID: 0000-0001-6200-2448, Bell‐Simons, Michael ORCID: 0000-0003-0681-901X, Kluge, Lena, Cagmak, Cagla, Klimek, Jennifer, Haag, Natja, Iohan, Lukas C., Coulon, Audrey, Costa, Marcos R. ORCID: 0000-0002-4928-2163, Kilinc, Devrim ORCID: 0000-0003-3321-5203 and Zempel, Hans ORCID: 0000-0002-7510-3077 (2025). 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, 21 (5). Wiley. ISSN 1552-5260

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Abstract

[Artikel-Nr.: 21:e14403] 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. Highlights: Tau knockout alters neurite growth and axon initial segment formation in human neurons. Tau isoforms show differential axonal localization in human neurons. Tau depletion protects against amyloid beta oligomer (AβO)–mediated neurotoxicity. 1N4R tau mediates AβO‐induced toxicity in human neurons.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Buchholz, Sarah UNSPECIFIED https://orcid.org/0000-0002-3636-1364 UNSPECIFIED Kabbani, Mohamed Aghyad Al UNSPECIFIED https://orcid.org/0000-0001-6200-2448 UNSPECIFIED Bell‐Simons, Michael UNSPECIFIED https://orcid.org/0000-0003-0681-901X UNSPECIFIED Kluge, Lena UNSPECIFIED UNSPECIFIED UNSPECIFIED Cagmak, Cagla UNSPECIFIED UNSPECIFIED UNSPECIFIED Klimek, Jennifer UNSPECIFIED UNSPECIFIED UNSPECIFIED Haag, Natja UNSPECIFIED UNSPECIFIED UNSPECIFIED Iohan, Lukas C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Coulon, Audrey UNSPECIFIED UNSPECIFIED UNSPECIFIED Costa, Marcos R. UNSPECIFIED https://orcid.org/0000-0002-4928-2163 UNSPECIFIED Kilinc, Devrim UNSPECIFIED https://orcid.org/0000-0003-3321-5203 UNSPECIFIED Zempel, Hans UNSPECIFIED https://orcid.org/0000-0002-7510-3077 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-800947
Identification Number:	10.1002/alz.14403
Journal or Publication Title:	Alzheimer's & Dementia
Volume:	21
Number:	5
Number of Pages:	22
Date:	28 May 2025
Publisher:	Wiley
ISSN:	1552-5260
Language:	English
Faculty:	Central Institutions / Interdisciplinary Research Centers Faculty of Medicine
Divisions:	Faculty of Medicine > Humangenetik > Institut für Humangenetik Zentrum für Molekulare Medizin
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language axon initial segment ; Alzheimer’s disease ; amyloid beta ; human induced pluripotent stem cells ; induced neurons ; isoforms ; knockout ; neuronal activity ; tau ; tauopathy English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80094