While Alzheimer’s disease (AD) is the leading cause of dementia in older adults, and a growing health concern in our aging society, there is a remarkable subset of people who seem immune to age-related cognitive decline and AD-associated pathology. This subset is made up of centenarians, individuals who live beyond 100 years, and cognitive superagers, individuals over the age of 80 who maintain exceptional cognitive health. These individuals often have resistant brains that show little or no Alzheimer’s pathology, or resilient brains that maintain cognitive health despite the presence of Alzheimer’s pathology. The cellular and molecular mechanisms that protect these individuals remain largely unknown, particularly in microglia, the brain’s immune cells that help maintain brain health and respond to disease.
To explore this, Drs. Park and Kim, in collaboration with the New England Centenarian Study group (led by Dr. Thomas Perls, Boston University), have developed a unique model system that reprograms blood cells from centenarians, cognitive superagers, and age-matched controls into microglia (iMGLs). During the reprogramming process, the age of the iMGLs is “reset” while preserving their genetic background. This enables the Park and Kim labs to compare microglial function across individuals of different ages and with varying pathologies. To date, they have successfully generated and validated 17 microglial cell lines from these cohorts, with additional lines in development. Preliminary analyses of these centenarian-derived microglia revealed distinct genetic and functional signatures compared to controls. In particular, the team identified a striking increase in the production of neprilysin, an enzyme that degrades amyloid, one of the toxic proteins that accumulates in AD. Normally, neprilysin levels decline with age, which possibly contributes to the buildup of amyloid beta. However, in microglia from select centenarians and cognitive superagers, neprilysin levels were significantly elevated. Functional experiments confirm that these microglia were more efficient at clearing amyloid in the 3D Alzheimer’s-in-a-Dish cell culture model. These findings suggest that enhanced neprilysin activity may be one way in which centenarians’ brains resist Alzheimer’s pathology. Building on these discoveries, the team hypothesizes that an increased production of neprilysin in centenarian-derived microglia confers resistance to AD by enhancing amyloid clearance and preserving microglial balance in subjects with exceptional longevity and brain resilience/resistance.
They will test this hypothesis through two experimental aims. In the first aim, they will utilize a 3D human cell culture model, combining neurons, astrocytes, and microglia, to test whether knocking out neprilysin in centenarian microglia reduces their ability to clear amyloid and protect neurons from tau pathology and inflammation. In the second aim, they will utilize single-cell RNA sequencing to compare gene expression patterns across centenarian and control microglia to identify the molecular pathways underlying resilience and resistance, beyond neprilysin. This work is among the first to directly test how microglia from individuals with extreme longevity may protect the brain from AD. By identifying the genetic and cellular mechanisms that enable centenarian microglia to resist pathology, this study could uncover novel therapeutic targets that mimic natural resistance and resilience to promote healthy brain aging.
