Aging is associated with a loss of cognitive function related to learning, memory, and executive function with varying severity. Although there is no age-related loss of neurons in healthy aging, myelin damage accumulates and is associated with cognitive decline. The brain’s resident macrophages, microglia, are responsible for clearing damaged myelin and promoting subsequent oligodendrocyte-mediated remyelination. To test the hypothesis that age-related dysfunction of microglial phagocytosis and oligodendrocyte remyelination capacity contributes to myelin pathology and cognitive impairment. To test this, rhesus monkeys from across the lifespan (7-30 years of age) were tested in three specific aims. 1) To characterize gene expression of myelin basic protein (MBP) in the brain and clearance of MBP to the cerebrospinal fluid (CSF) in relation to age-related myelin pathology. The density of myelinated axons visualized using label-free spectral confocal reflectance imaging did not correlate with age, but was significantly lower in aged animals with cognitive impairment. Next, MBP gene expression was measured using qPCR in the dorsal prefrontal cortex along with quantification of MBP protein levels in the CSF using ELISA. Age-dependent increases of MBP gene expression in the brain and MBP protein levels in the CSF were observed. Interestingly, MBP levels in the CSF were lower in animals with cognitive impairment. 2) To test the hypothesis that microglia would become increasingly primed for phagocytosis with age-related myelin pathology. The number of microglia immunostained with galectin-3, a marker for phagocytic activation, was quantified in the frontal white matter and increases in both aging and cognitive decline were detected. 3) To evaluate the hypothesis that lipofuscin, an age-related accumulation indicative of autophagic dysfunction, would accumulate and impair glial cells of the white matter in aged animals. Lipofuscin accumulation was increased with age in the frontal white matter and the size of lipofuscin clusters was associated with cognitive impairment. Lipofuscin was found primarily in microglia and oligodendrocytes, but not in astrocytes. These data suggest that lipofuscin burden in microglia and oligodendrocytes inhibits their homeostatic functions resulting in improper myelin clearance and turnover, leading to a devastating feed-forward cycle of myelin damage that contributes to age-related cognitive impairment.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/29985 |
| Date | 12 June 2018 |
| Creators | Townsend-Shobin, Eli |
| Contributors | Rosene, Douglas L., Ikezu, Tsuneya |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NonCommercial 4.0 International, http://creativecommons.org/licenses/by-nc/4.0/ |
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