There may be new therapy options for illnesses like Alzheimer’s: Research

A recent study establishes a direct relationship between Piezo1, an ion channel that is mechanically activated, and intracellular cholesterol levels during neural development in neural stem cells. This study also reveals how mechanical forces and tissue mechanics affect the morphology of the developing brain.

The research was published today in the Journal of General Physiology under the headline, “Piezo1 controls cholesterol biosynthesis to alter neural stem cell destiny throughout brain development.” The results of the study show that Piezo1 is involved in the neurodevelopmental process that controls cellular cholesterol metabolism to modify the number, quality, and arrangement of cells.

According to Medha Pathak, PhD, an assistant professor in the Department of Physiology & Biophysics at the UCI School of Medicine, “Our unexpected finding linking Piezo1 and cholesterol also motivates investigations for Piezo1 in neurodegenerative diseases linked to cholesterol homeostasis, such as Alzheimer’s Disease.” “We may be able to create innovative therapy for some of these disorders by modulating Piezo1 activity through medicines,” said the researcher.

The orchestration of several complicated processes during a number of stages of neural development results in the formation of the brain and spinal cord. Cells replicate, form structures, and interact with other cells as the brain grows. These processes generate mechanical forces that further mould brain architecture, but it is unclear how cells pick up on these mechanical signals.

“We previously discovered that human foetal brain-derived neural stem/progenitor cells activate Piezo1 channels in response to both externally applied and cell-generated mechanical forces, and we now show in our current study thatPiezo1 is important for proper brain development,” said Jamison Nourse, PhD, assistant project scientist in the Department of Physiology & Biophysics and study’s first author. “Through our research, we identified a unique relationship between Piezo1 and cholesterol production, opening up new directions for research into how mechanical forces affect lipid metabolism in the brain,” the authors write.

In many physiological systems, including vascular development, cardiovascular homeostasis, lymphatic development, red blood cell volume regulation, the baroreceptor response in neurons, cartilage mechanics, bone formation, macrophage polarisation responses, keratinocyte migration in wound healing, and neural stem cell fate, the Piezo family of mechanically-activated ion channels has been shown to play a role in mechanotransduction. For his ground-breaking discovery of the Piezo channels, Dr. Ardem Patapoutian of The Scripps Research Institute in San Diego was given the Nobel Prize in Physiology or Medicine in 2021.

According to Pathak, improper brain development can result in deformities and functional problems that last a lifetime. Furthermore, “our study offers fresh ways for understanding how brain problems may originate,” despite the fact that “we still do not understand the cause behind many brain developmental disorders.”

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Piezo1 and its impact on cholesterol metabolism in both early human brain development and adult-onset neurodegenerative disorders are still being studied by Pathak and her research team.

The National Institutes of Health provided funding for this endeavour.

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