hiPSC-neurons recapitulate the subtype-specific cell intrinsic nature of susceptibility to neurodegenerative disease-relevant aggregation

• DOI: 10.1186/s40478-025-02000-4
• Publication Date: 2025-05-19T09:08:20Z
• Authors: Ian Weidling; Christina N. Preiss; Sarah E. Chancellor; Gyan Srivastava; Lauren Gibilisco; Gen Lin; Melanie Shackett ...; Janice Lee; Lindsay M. Roth; Olga Morozova; Kyong Nyon Nam; Nehal R. Patel; Qing Liu; J. K. Thomas; Peter Reinhardt; Ruven Wilkens; Dagmar E. Ehrnhoefer; Andreas Striebinger; Stefan Barghorn; Christina Xanthop...; Marie-Theres Weil; Sandra Biesinger; Miroslav Cik; Nandini Romanul; Kiran Yanamandra; Alessandra M. Welker; Jessica Wu; Laura Gasparini; Jan Stöhr; Xavier Langlois; Justine D. Manos

Alzheimer's disease (AD) is characterized by the accumulation and spread of Tau intraneuronal inclusions throughout most telencephalon, leaving hindbrain regions like cerebellum spinal cord largely spared. These neuropathological observations, along with identification specific vulnerable sub-populations from AD brain-derived single nuclei transcriptomics, suggest that a subset brain neuronal subtypes possess selective vulnerability to pathology. Given inability culture neurons patient brains, disease-relevant in vitro model which recapitulates these features would serve as critical tool validate modulators resilience. Using our recently established platform for inducing endogenous aggregation human induced pluripotent stem cell (hiPSC)-derived cortical excitatory via application exogenous aggregates, we explored whether aggregates preferentially induce subtypes. We compared seeding hiPSC-derived neuron representing regional identities across forebrain, midbrain, hindbrain. Higher susceptibility (i.e. more aggregation) was consistently observed among subtypes, CTIP2-positive, somatostatin (SST)-positive inhibitory showing greatest levels hiPSC lines multiple donors. hiPSC-neurons also delineated between disease-specific vulnerabilities different protein α-synuclein preformed fibrils showed an increased propensity midbrain dopaminergic (mDA)-like neurons, mimicking Parkinson's (PD)-specific susceptibility. Aggregate uptake degradation rates were insufficient explain differential The absence consistent transcriptional response following aggregate further indicated intrinsic subtype-specific properties could drive present data provides evidence exhibit manifest autonomous manner, suggesting mining (or basal) transcriptomic signatures resilient uncover molecular underpinnings found variety neurodegenerative diseases.