A scalable human neuron model of Alzheimer's disease relevant tauopathy reveals mechanisms linking Tau fibrillization to synaptic dysfunction

Alzheimer's disease is a tauopathy, a condition caused by the abnormal buildup of hyperphosphorylated Tau protein. This protein clumps together, damaging synaptic connections, disrupting nerve signaling, and leading to mental decline. To better understand this process and find treatments, researchers have created two human iPSC-derived neuron models.

One model starts with pre-formed Tau fragments, while the other overexpresses Tau to speed up pathology. Both models mirror key aspects of tauopathy, such as the accumulation of toxic Tau aggregates and the breakdown of synapses and neurons.

Cryo-electron tomography (cryo-ET) showed the shape of Tau fibrils within cells and how they entangle synaptic vesicles. Through this model, scientists analyzed phosphoproteomics, high-content screening, and functional tests to uncover the pathways fueling Tau aggregation. They found that early in the process, Tau's microtubule-binding domain gets phosphorylated by MARK2, sparking the formation of protein clumps.

They also discovered that small molecules that target the PI3K/mTOR/GSK3 pathway can slow down aggregation and restore synaptic function. By lowering the phosphorylation at specific points on Tau, these molecules can potentially disrupt the aggregation cascade and offer new therapeutic targets.