The Alzheimer's disease-associated rs28834970 variant in PTK2B impairs electrical activity and regulates Tau phosphorylation and APP processing in human neuronal cultures

The rs28834970 C risk allele in PTK2B is linked to >80% reduced total PYK2 levels and increased activated PYK2 phosphorylation in human neuronal cultures.

• Why it matters: PTK2B/PYK2 is a genetic AD risk factor, but how its causal variant affects amyloid, tau, and neuronal dysfunction is unclear.
• What they did: Using in silico prioritization plus luciferase assays, the rs28834970 regulatory variant was modeled in CRISPR-Cas9 isogenic KOLF2.1J iPSCs and differentiated into human neuronal cultures, then assessed with immunoblotting, RNA-seq, MEA, microfluidic synapse imaging, and Tau/APP assays.
• The result: In rs28834970 CC neurons, network recruitment and burst organization were altered, dendritic development and postsynaptic maturation were impacted, Tau phosphorylation at multiple pathological sites increased, and APP processing shifted toward higher sAPP, sAPPβ, and Aβ with lower APP and CTF.

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