Tracing Alzheimer’s disease back to development

Alzheimer’s disease (AD) is classically understood as a neurodegenerative disease that comes with advanced age. But in a new study published in Stem Cell Reports, Jenny Hsieh, a stem cell researcher at the University of Texas at San Antonio, and her team reported evidence that AD might take root in the brain during the earliest phases of development (1). Their findings suggest that these early changes might set the stage for the eventual destruction of brain tissue characteristic of AD.

To model the effects of AD in early development, Hsieh’s team cultured brain organoids using induced pluripotent stem cells in a dish. They used CRISPR-Cas9 to introduce genetic mutations associated with familial AD, which is a rare early-onset form associated with a single gene and passed down through generations. Most familial AD cases are caused by mutations in the presenilin1 (PSEN1) gene, so the research team studied three different PSEN1 mutations in brain organoids and compared them to organoids without any PSEN1 mutations.

As they watched the brain organoids grow, they were surprised to discover that organoids bearing the PSEN1 mutation changed in appearance quickly. As early as two weeks after the cultures were established, the mutation-bearing organoids were much bigger than their counterparts. “What really struck us — and we were not expecting this — is with this particular presenilin1 mutation [L435F] … the organoids, instead of being perfectly circular, showed this unusual morphology,” said Hsieh. 

Further studies showed that the PSEN1 L435F mutation increased the number of neural progenitor cells in the organoids. These cells usually differentiate into multiple types of brain cells, but in this case, they remained in their early state. This led to fewer neurons in the organoid overall. With more digging, Hsieh’s team discovered that the PSEN1 L435F mutation led to increased activation of the Notch signaling pathway that kept progenitor cells from becoming neurons. By inhibiting a key step in the Notch signaling pathway, the researchers discovered that the progenitor cells could finally turn into neurons.

Alzheimer's disease may begin earlier than we thought. 
– Jenny Hsieh, University of Texas at San Antonio

“The most exciting aspect of this paper was this morphology,” said Hsieh. “We could use organoids in vitro to capture these developmental changes that would be impossible to see in a developing brain in utero.” 

The results suggest a need for a precision medicine approach to AD treatments, even for patients who have mutations in the same gene. “For every one of these patients, even with familial Alzheimer's disease, the mutation is very unique,” said Hsieh. She added that patients with early-onset Alzheimer’s disease cannot be lumped together in clinical trials because important differences may be missed. “It's very possible they're going to respond to drugs differently,” said Hsieh.

Based on their findings, developing treatments that target the early neurodevelopmental effects of AD may be beneficial, according to Hsieh. “We often say [that AD] is an age-related disorder, but maybe we need to think more broadly,” said Hsieh. “Alzheimer's disease may begin earlier than we thought.”

References

1. Hurley, E. M., Mozolewski, P., Dobrowolski, R. & Hsieh, J. Familial Alzheimer’s disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling. Stem Cell Reports 18, 1516–1533 (2023).