The "Trans-Cellular Prion-Like Propagation of Transcriptional Memory" Model

Rather than treating cell-type specific expression patterns as static features, I propose that SEA-AD involves a propagating wave of epigenetic “conditioning” wherein neurons that encounter tau or amyloid oligomers undergo reversible chromatin remodeling (through BRG1/BAF complex and polycomb repression shifts), establishing a temporary but communicable transcriptional state that can be transferred to naive neighboring cells via extracellular vesicles (EVs) carrying modified histone reader proteins and non-coding RNAs. This would mean that apparent cell-type specificity reflects not intrinsic cellular identity, but rather spatial-temporal “infection” of transcriptional state. Microglia, which efficiently internalize pathological EVs, would become secondary propagators—not primary drivers—of neuroinflammatory gene expression. Testable predictions: (1) EVs from tau-exposed neurons (in vitro or

Debate provenance: derived from debate debate-seaad-20260402 on question: Cell-type specific expression patterns of neurodegeneration genes in SEA-AD. Consensus signal: domain_expert, skeptic, theorist discussed the mechanism terms BRG1/BAF, Memory, Model, Prion-Like, Propagation, SEA, Trans-Cellular, Transcriptional. Novelty signal: skeptic-discussed-counterarguments.