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

Alzheimer’s Dement

2025

Alzheimer's disease

Amyloid beta

Axon initial segment

Human induced pluripotent stem cells

Induced neurons

Isoforms

Knockout

Neuronal activity

Tau

Tauopathy

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