hiPSC neurons recapitulate the cell intrinsic nature of susceptibility to Alzheimers disease relevant tau aggregation

Alzheimers disease (AD) is characterized by the accumulation of tau pathology first in the entorhinal cortex, followed by gradual spreading throughout the cortex, leaving hindbrain regions like the cerebellum and spinal cord largely spared. These neuropathological observations suggest that specific brain regions, and perhaps neuronal subtypes, possess a selective vulnerability to tau pathology. We recently established a method for inducing endogenous tau aggregation using sarkosyl-insoluble tau seeds derived from AD brains in human induced pluripotent stem cell (hiPSC)-derived cortical excitatory neurons. Here, we applied this model to ask whether different neuronal subtypes respond similarly to the application of exogenous tau seeds in the absence of non-neuronal cell types. A comparison of tau seeding in five hiPSC-derived neuronal subtypes representing regional identities across the forebrain, midbrain and hindbrain consistently revealed higher vulnerability (i.e. more aggregation) among cortical neuron subtypes, with CTIP2+ SST+ cortical inhibitory neurons showing the most highest aggregation across multiple donor hiPSC lines. Bulk RNA-seq did not detect consistent transcriptional responses following tau seeding, suggesting that in steady state, cell intrinsic properties underlie the differences observed in aggregation propensity. Baseline transcriptional differences between tau-vulnerable and tau-resilient hiPSC-neurons revealed changes in synaptic and ion transport gene expression. The ability to link these changes back to AD patient tissue data provides evidence that hiPSC-neurons can enable modeling of a fundamental aspect of AD , namely selective vulnerability, despite their young age, and highlights opportunities for future studies into mechanisms determining susceptibility to tau aggregation