Investigating the role of tau loss‐of‐function in Alzheimer’s Disease pathogenesis

Abstract

AbstractBackgroundOne hallmark of Alzheimer’s Disease (AD) pathology is hyperphosphorylation of tau protein, which leads to loss of its normal function and promotes aggregation into neurotoxic fibrillary tangles. While tau gain‐of‐toxic function is well‐documented, the exact role of tau loss‐of‐function in AD pathogenesis remains uncharacterized. We hypothesize that tau loss‐of‐function contributes to AD pathogenesis by activating the cellular stress response in neurons and astrocytes, characterized by cytoplasmic double‐stranded RNA (dsRNA) release, stress granule formation, and inflammation.MethodWe generated human induced pluripotent stem cell (hiPSC)‐derived mixed cortical cultures and primary human fetal astrocyte cultures, allowing us to model the earliest stages of AD pathogenesis in a uniquely human system. In these cultures, we depleted tau through lentiviral transduction and CRISPR‐Cas9 to model acute and chronic loss‐of‐function, respectively. We utilized quantitative real‐time polymerase chain reactions, enzyme‐linked immunosorbent assays, and immunocytochemistry to investigate the expression of genes and proteins implicated in stress and inflammation.ResultPreliminary results indicate upregulation of genes and proteins associated with inflammation and stress granule formation in tau‐depleted neurons and astrocytes. Tau‐depleted cortical cultures exhibit increased secretion of chemoattractant cytokines, and tau‐depleted astrocytes demonstrate increased glial fibrillary acidic protein expression suggestive of non‐cell autonomous pro‐inflammatory cytokine induction. Further, tau‐depleted neurons show increased levels of stress chaperones and cytoplasmic dsRNA known to induce stress granules.ConclusionTau loss‐of‐function may contribute to AD pathogenesis through promoting the release of double‐stranded RNA into the cytoplasm, stress granule formation, and inflammation.