The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction.

ABSTRACT:

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 oligo

SUBMITTER: Buchholz S 

PROVIDER: S-EPMC12089071 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature