Tau depletion in human neurons mitigates Aβ-driven toxicity

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaques and tau tangles.
• Aβ toxicity is known to be tau-dependent in mouse models.
• Human cellular models for chronic tau lowering are lacking.

Purpose of the Study:

• To create and utilize human induced pluripotent stem cell (iPSC) models with chronic tau depletion.
• To investigate the role of tau in Aβ-induced neuronal dysfunction and neurodegeneration in human cells.

Main Methods:

• Generated isogenic human iPSC panels with tau depletion using CRISPR-Cas9.
• Differentiated iPSCs into cortical neurons and co-cultured with astrocytes.
• Assessed neuronal activity, synaptic density, neurite outgrowth, mitochondrial transport, and neurodegeneration.

Main Results:

• Tau depletion reduced neuronal activity but did not affect synaptic density.
• Tau depletion protected neurons from Aβ-induced hyperactivity and mitochondrial transport deficits.
• Tau depletion mitigated Aβ-induced neurodegeneration.

Conclusions:

• Tau is essential for Aβ-driven neurotoxicity in human neurons.
• Chronic tau lowering strategies demonstrate protective effects against AD pathogenesis.
• Developed human iPSC models offer a platform for further AD research.