Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. However, the exact cause of AD remains unknown. Existing approved treatments for AD are designed to target the already existing AD neuropathology, potentially limiting their effectiveness as they may be administered too late to see significant effects. Now, researchers at the University of Texas at San Antonio report they have created a stem cell model of human brain development that may pave the way for studying AD in its early stages and may potentially identify more preventative treatments.
The findings are published in Stem Cell Reports in an article titled, “Familial Alzheimer’s disease associated PSEN1 mutations affect neurodevelopment through increased Notch signaling.”
“AD is the most common neurodegenerative disorder, but its root cause may lie in neurodevelopment,” the researchers wrote. “PSEN1 mutations 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.”
Jenny Hsieh, PhD, professor at the University of Texas at San Antonio, and colleagues sought to determine how AD-associated gene mutations affect early human brain development. The researchers grew cortical spheres, which are small clumps of cells resembling human embryonic brains, from CRISPR-edited stem cell lines harboring fAD mutations.
AD mutations interfered with normal development of these cortical spheres, whereby mutant spheres were larger and contained less mature and functioning neurons compared to cortical spheres without the mutations.
By pinpointing the underlying molecular pathways, the researchers could identify points of intervention to restore normal brain development in their cortical sphere model.
“In summary, we find that, in heterozygous PSEN1 L435F hCSs, there are deficits in neuronal differentiation caused by dysregulated Notch signaling at an early stage in neurodevelopment,” concluded the researchers. “We show an early reduction in neurons and an increase in cortical volume many years before any behavioral symptoms would manifest. This may provide a potential therapeutic target for innervation and stopping AD before it begins, treating the causes rather than the consequences of AD.”
