Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling

Alzheimer's disease (AD) is the most common neurodegenerative disorder, but its root cause may lie in neurodevelopment. PSEN1 mu-tations cause the majority of familial AD, potentially by disrupting proper Notch signaling, causing early unnoticed cellular changes that affect later AD progression. While rodent models are useful for modeling later stages of AD, human induced pluripotent stem cell-derived cortical spheroids (hCSs) allow access to studying the human cortex at the cellular level over the course of development. Here, we show that the PSEN1 L435F heterozygous mutation affects hCS development, increasing size, increasing progenitors, and decreasing post -mitotic neurons as a result of increased Notch target gene expression during early hCS development. We also show altered A8 expression and neuronal activity at later hCS stages. These results contrast previous findings, showing how individual PSEN1 mutations may differ-entially affect neurodevelopment and may give insight into fAD progression to provide earlier time points for more effective treatments.