W40 - The Mechanosensitive Piezo1 Ion Channel Induces Microglial Lipid Accumulation

Saturday, October 11, 2025

10:00 AM - 11:00 AM PDT

Location: Exhibit Hall F, G & H

Presenting Author(s)

GT

Gianna Tan

Undergraduate
University of California - Irvine, United States

Co-Author(s)

ML

Man Yi Lee

Student
University of California - Irvine, United States
Thuy-Khanh Tran-Dao

Graduate Student Researcher
UC Irvine
Irvine, California, United States
Daanish Kulkarni

Graduate Student Researcher
UC Irvine
Irvine, California, United States

Primary Investigator(s)

Wendy F. Liu, PhD

Professor
University of California, Irvine
Irvine, California, United States

Introduction: : Alzheimer’s disease (AD) is the most common form of dementia and impacts around six million Americans. By 2050, this number is projected to increase to 13 million people. While one of the main hallmarks of AD is the accumulation of amyloid beta plaques, recent studies have shown that dysfunctional microglia, the resident immune cells of the brain, drive the progression of AD neuropathology. During early stages of AD, microglia aid in the clearance of plaques, however prolonged activation results in lipid accumulation and subsequent lipid-droplet accumulating microglia, or LDAMs, that are dysfunctional and further progress the disease. One characteristic of amyloid plaques is that they are significantly stiffer than the surrounding tissue. Piezo1 is a mechanosensitive ion channel that is activated by changes in tissue stiffness, and recent literature has shown Piezo1-mediated mechanosensation is crucial to microglia migration, inflammatory cytokine secretion, and crucially the clearance of amyloid. Thus far the connection between Piezo1 activation and lipid accumulation in plaque associated microglia hasn’t been elucidated. Our objective is to show that the activation of microglial Piezo1 directly leads to an increase in lipid droplet accumulation and Piezo1 expression levels affect levels of proteins related to cholesterol/triglyceride synthesis and lipid droplet formation.

Materials and

Methods: : BV2 and human microglia (iMGLs, differentiated from stem cells) were induced to an inflammatory state with LPS, or disease associated microglia (DAM) state with Aβ respectively, followed by Yoda1 treatment. Stiffness experiments on BV2 cells were conducted using 1kpa and 280 kpa polyacrylamide hydrogels to mimic a healthy or plaque-associated tissue. Confocal microscopy and flow cytometry were used to determine the number of lipid droplets per cell and visualize lipid droplets, while western blots and qPCR were used to investigate the effect of Piezo1 on gene and protein expression of proteins related to lipid biosynthesis or lipid droplet formation. We additionally analyzed previously archived RNAseq data between wildtype and Piezo1 knockout microglia in mice.

Results, Conclusions, and Discussions:: We have found that the activation of Piezo1 with Yoda1 induces lipid droplet accumulation in BV2 cells (Fig. 1). Stiff substrate induced Piezo1 activation was also found to cause lipid accumulation (Fig. 2). Decreased expression of Piezo1 also downregulates many genes responsible for lipid metabolism in both BV2 and human microglia, such as Dgat1 and Hmgcs1, which are responsible for synthesis of triglycerides and cholesterol respectively. Piezo1 activation also causes lipid droplet accumulation in human iMGLs in a dose dependent manner when treated with amyloid beta (Fig. 3).

Our studies have shown that mechanical activation of Piezo1 modulates lipid dynamics in microglia by inducing its accumulation in both mice and human microglia. Decreased expression of Piezo1 is also responsible for the downregulation of crucial genes involved with microglial lipid accumulation. This supports previous research showing LDAMs being exclusive to plaque-associated microglia and directly implicates Piezo1 activation, from interaction with stiff plaques, as an important initiator of lipid accumulation. To assess the composition of these lipids we are currently performing LC-MS to determine whether Piezo1 specific lipid accumulation leads to the accumulation of the same lipid species reported in dysfunctional LDAMs. We are additionally performing glucose tracing studies to definitively determine whether lipid accumulation is due to biosynthesis.

Acknowledgements and/or References (Optional): : Funding from an NIH/NIA R21 AG069067 grant, NIH/NINDS T32 NS121727-01 grant, and support from NIH award S10OD0250264 for the Olympus FV3000 Confocal Microscope. Schematics created with BioRender.com