Universität zu Köln

Buchholz, Sarah ORCID: 0000-0002-3636-1364 (2023). Investigating human TAU isoform-specific functions and their toxicity in Alzheimer's disease and related tauopathies. PhD thesis, Universität zu Köln.

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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with rising prevalence, lacking effective treatments. Clinical symptoms include cognitive decline, memory loss, language impairments, and behavioral changes. On the molecular level, AD is characterized by the accumulation of amyloid beta (Aβ) and TAU in insoluble aggregates in the brain. While TAU is recognized as a key driver of disease progression, its underlying isoforms have not yet been thoroughly examined. Strikingly, changes in the abundance of the TAU isoforms alone can be sufficient to cause neurodegenerative diseases characterized by the pathological accumulation of TAU. We hypothesize that human TAU isoforms have differential functions in health and disease and may be of therapeutic value. Therefore, we aimed here to i) establish suitable neuronal cell models to study (isoform-specific) functions of human TAU, ii) analyze isoform-specific properties of TAU in a disease-relevant cellular context, iii) and investigate TAU-isoform mediated toxicity by modelling AD-like stress in human neurons to identify novel potential therapeutic targets for the treatment of AD. Our results provide evidence that: i) human TAU isoforms are differentially distributed in mature neurons, ii) all TAU isoforms can mediate MT assembly and stability in an isolated manner and to a similar extent in undifferentiated cells, iii) the regulation of neurite and AIS development represent novel functions of TAU that can be mediated by all six human specific TAU isoforms, iv) TAU depletion protects human neurons from Aβ-induced loss of neuronal activity demonstrating the key role of TAU in mediating Aβ-induced synaptotoxicity, and v) that one specific TAU isoform, 1N4R, mediates early TAU-mediated toxicity, which could significantly improve future treatment strategies for this currently untreatable and detrimental disease.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Buchholz, Sarah sarah.buchholz1@uk-koeln.de orcid.org/0000-0002-3636-1364 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-700613
Date:	2 June 2023
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	Faculty of Medicine > Humangenetik > Institut für Humangenetik Zentrum für Molekulare Medizin
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language TAU isoforms English Alzheimer's disease English Tauopathies English hiPSC-derived neurons English
Date of oral exam:	23 May 2023
Referee:	Name Academic Title Wiesner, Rudolf Prof. Dr. Gehring, Niels Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/70061