Early disruption of neurogenesis and neural architecture by amyloid β and Tau during Drosophila development

Alzheimers disease is recognized as a late-onset neurodegenerative disorder; however, accumulating evidence suggests that disease-associated proteins may exert deleterious effects much earlier during neural development. Using a Drosophila model expressing human amyloid-{beta} and Tau, we investigated the impact of these proteins on embryonic neurodevelopment and neural stem cell dynamics. Embryos expressing amyloid-{beta} and Tau exhibited pronounced defects in axonal patterning and compromised neuronal cytoskeletal integrity, indicating early disruption of neural architecture. We observed aberrant elevation and mislocalization of the cell fate determinant Prospero, leading to premature neuronal differentiation and disruption of progenitor lineage progression. Consequently, larval brains displayed a reduced number of Prospero-positive ganglion mother cells, reflecting impaired neuroblast lineage maintenance. Cell-cycle analysis using the FUCCI system revealed altered neuroblast cell-cycle dynamics, characterized by depletion of proliferative populations and enrichment of G1-phase cells, indicative of stem cell exhaustion. In addition, increased apoptotic signaling was detected in larval neural tissues expressing amyloid-{beta} and Tau. Together, our findings demonstrate that amyloid-{beta} and Tau disrupt asymmetric division, differentiation, and self-renewal of neural stem cells during development, resulting in reduced neuronal output and defective brain organization. This study highlights that amyloid-{beta} and Tau exert neurotoxic effects early in development, providing mechanistic insight into how neurodevelopmental perturbations may contribute to later neurodegeneration.