Abstract
AbstractBackgroundAPOE4 is the strongest genetic risk factor for Alzheimer’s disease with Tau pathology, namely hyperphosphorylation (p‐Tau) and aggregation of Tau into neurofibrillary tangles (NFTs) being correlated with poor cognitive outcomes in AD. Instances of mild traumatic brain injury (TBI) have been associated with increased susceptibility to neurodegenerative diseases such as AD and related dementias. We hypothesize that human APOE4 carriers’ brains are more susceptible to increased tau pathology with instances of TBI further increasing the severity.MethodUsing the 3D multi‐cellular integrated human brain (miBrain) model, which recapitulates key brain tissues through the co‐culturing of all hiPSC‐derived major brain cell‐types, Tau pathology can be induced with treatment of Tau fibrils or by increasing endogenous phosphorylated Tau with methotrexate.ResultAPOE4/4 miBrain cultures exhibit increased Tau pathology compared to isogenic APOE3/3 miBrains. Combinatorial genetic mixing experiments revealed that the increase of Tau hyperphosphorylation is dependent on the presence of APOE4 microglia.ConclusionData suggests that microglia facilitate the accumulation of p‐tau in APOE4 genetic backgrounds in an in vitro 3D model.
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