Impact of Tau Overexpression on DNA Replication Dynamics in Centromeres of Human Neural Progenitor Cells

Aging somatic cells are characterized by specific chromosome aneuploidy. This work examines the role of DNA replication within the centromeres of chromosomes Y (ChrY) and 21 (Chr21). The aneuploidy of these two chromosomes is associated with Alzheimer's Disease (AD) pathology. Using human neural progenitor cells engineered to overexpress wild-type (wt) and pseudo-hyper-phosphorylated (php) Tau proteins, we developed a novel method to analyze replication dynamics in centromeric regions. Our findings reveal overexpression reduces the replication initiation events that are active within alpha satellite sequences in control condition. Mass spectrometry analysis on immunoprecipitated Tau identified nuclear interactors of Tau, particularly in its php form, which might directly influence chromatin architecture and gene expression. This research provides critical insights into the molecular mechanisms of aneuploidy in tauopathies.