Exploring the Impact of Aging-Related Mechanical Changes in the Brain on Microglial Activities and Their Implications for Alzheimer's Disease Progression

Alzheimer’s disease (AD) is the most prevalent neurodegenerative condition, with its effects becoming more pronounced with age, suggesting that aging is a critical factor in its development. Recent clinical observations have identified significant mechanical changes in the aging brain, including decreased stiffness, which reflects tissue rigidity, and increased viscoelasticity, which describes fluidic and time-dependent properties. These alterations primarily result from reduced tissue connectivity with age. However, their precise effects on brain cells remain unclear. This project focuses on microglia, the brain’s primary immune cells, which play a crucial role in maintaining brain health by responding to inflammation, clearing debris, and repairing damage. Their function is particularly important in AD, where they contribute to both inflammatory responses and disease progression. Despite growing recognition of the interplay between mechanics and cellular function, how aging-induced mechanical changes affect microglial behavior remains poorly understood. Investigating this relationship could provide valuable insights into AD pathogenesis and inform the development of targeted therapeutic strategies. The overarching goal of this project is to elucidate how matrix mechanics—specifically stiffness and viscoelasticity—shape microglial function and behavior, and to explore their implications for AD progression at the cellular and molecular levels. Our central hypothesis is that mechanical changes in the aging brain reshape microglial activity, promoting inflammatory characteristics that exacerbate AD pathology. To test this hypothesis, this research is structured around three specific aims: 1) engineer a 3D in vitro model that closely replicates the brain’s extracellular matrix (ECM) with independent control over stiffness and viscoelasticity, 2) investigate how variations in matrix mechanics influence microglial function, particularly their inflammatory response and ability to clear debris, and 3) decipher the mechanotransduction pathways through which mechanical properties regulate microglial activity, identifying key molecular mechanisms involved. By integrating a multidisciplinary approach, this project explores AD from a novel mechanobiological perspective. Successful completion of these aims will deepen our understanding of AD, advance research on brain aging and mechanobiology, and potentially lead to innovative diagnostic and therapeutic strategies, particularly by targeting mechanotransduction pathways. Project Number: 1R03AG093279-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Sungmin Nam | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $284,108 | Activity Code: R03 | Study Section: Bioengineering and Tissue Engineering for Neuroscience Study Section[BTEN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298547