Not(ch) Just Development: Role of Notch Signaling in Neurodegeneration

Hurley, Erin
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Alzheimer’s disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms causing AD are yet to be fully understood. Familial AD (fAD) provides a useful model into uncovering these mechanisms, as autosomal dominant inherited mutations in PSEN1, PSEN2, or APP cause AD. PSEN1 accounts for over 90% of fAD and is the catalytic component of the gamma secretase. Because of this, there are several mechanisms by which mutations in PSEN1 can cause AD. One such mechanism is through neurodevelopment; the gamma secretase cleaves the Notch1 protein and regulates neuronal differentiation during neurodevelopment. Thus, mutations in PSEN1 may cause early unnoticed alterations during neurodevelopment that go on to present as AD pathology later in life. While rodent models are useful for modeling later stages of AD, human induced pluripotent stem cell-derived cortical spheroids (hCS) allow access to studying the human cortex at the cellular level over the course of development. Here, I show 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. I also show altered Aß expression and neuronal activity at later hCS stages. Aspects of these phenotypes are rescued using a Notch1 cleavage blocker in PSEN1 L435F hCS. Lentiviral techniques were also employed to overexpress the NICD in hCS lacking PSEN1 mutations to attempt to recapitulate phenotypes caused by the PSEN1 L435F mutation. These results contrast previous findings of the role of other PSEN1 mutations in proper neurodevelopment and neuronal differentiation, exhibiting how individual PSEN1 mutations may differentially affect neurodevelopment, and may give insight into fAD progression to provide earlier timepoints for more effective treatments.

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Alzheimer's disease, neurodegeneration, neurodevelopment, organoid, Presenilin1, stem cells
Neuroscience, Developmental and Regenerative Biology