Grant: Project Grant

As we age, our ability to think, reason, and remember decreases, a process called 'cognitive decline'. Some individuals have worse cognitive decline than others, impacting quality of life and increasing risk of dementia. As there are no drugs to improve brain function with aging, we need to better understand the cells and molecules involved in cognitive decline. Healthy cognition requires myelin - a substance surrounding nerves in the brain needed for nerve survival and function, which is made by cells called oligodendrocytes. Learning and memory in youth requires making more myelin and oligodendrocytes. In elderly individuals, however, brain areas enriched in myelin show abnormalities on MRI, with more abnormalities linked with worse cognitive decline. Therefore, changes in myelin and oligodendrocytes could cause cognitive decline with aging, however this has not yet been investigated. Here, we ask how myelin and oligodendrocytes change to cause cognitive decline with aging. We will analyze brains from aged individuals where we have measured cognitive decline over 15 years before passing, alongside using mice to test the consequence of changes in myelin and oligodendrocytes with aging. We will ask the following questions. First, because different brain regions control different features of cognition, which regions show changes in myelin and oligodendrocytes with age? Second, why do oligodendrocytes increase in individuals with cognitive decline, i.e. are more oligodendrocytes born or surviving? Third, how do changes in myelin and oligodendrocytes influence nerve loss and cognitive decline in aging? Can we target this therapeutically? This will tell us where the problematic myelin and oligodendrocyte changes occur in the aging brain, the cell behavior and molecules causing these changes, and the consequences on nerves and cognition. This will form the basis for therapeutic targeting of oligodendrocytes and myelin to ensure healthy cognition in aging.