Inflammation contributes to metabolic syndrome, including insulin resistance and atherosclerosis. Further, metabolic syndrome represents a risk factor for age-related dementias. This proposal focuses on the role of MyD88, required for signaling from cytokine and Toll Like Receptors. We showed that selective deletion of MyD88 from myeloid cells virtually eliminated diet-induced metabolic syndrome in obese mice. Here we extend this research to effects of inflammatory signaling for age-related cognitive decline in aging obese mice with or without metabolic syndrome. The present proposal addresses the hypothesis that deleting MyD88 from all CD11b+ myeloid cells will ameliorate age-related cognitive impairment in mice with obesity but without metabolic syndrome. Furthermore, we propose that selective deletion of MyD88 from microglia will also reduce age-related cognitive impairment in mice with metabolic syndrome, without affecting the systemic syndrome. Importantly, MyD88 appears functionally orthologous in humans and mice, and its absence does not cause unacceptable immunodeficiency suggesting the pathway is potentially druggable.
The specific aims are: 1. Establish whether ameliorating metabolic syndrome in MyD88fl/fl::CD11bCre mice on high-fat diet (HFD) is associated with improvement of age-related cognitive change. MyD88fl/fl::CD11bCre mice will be placed on HFD or chow and undergo serial behavior testing as well as hippocampal long-term potentiation (LTP). Pathological analyses of peripheral and CNS tissues will be performed. These data will address whether declining cognition is ameliorated in aging mice fed HFD by blocking innate immune reactions of myeloid cells and reducing metabolic syndrome systemically. 2. Determine if reduced microglial reaction in tamoxifen-injected MyD88fl/fl::CX3CR1(ER)-Cre mice on high-fat diet (HFD) improves age-related cognitive change. We anticipate that MyD88fl/fl::CD11bCre mice lacking myeloid-cell MyD88 will show improved age-related cognition as compared to controls. The mechanisms however could be exerted either systemically, in the CNS or both. The CX3CR1(ER)-Cre driver efficiently deletes 'floxed'targets from CX3CR1+ cells, and recombination is highly-selective for microglia by about one month after induction. MyD88fl/fl::CX3CR1(ER)- Cre mice will receive tamoxifen to induce recombination and will be placed on HFD or chow. Mice will be subjected to serial behavior testing and hippocampal LTP as in Aim 1. Focused pathological and immunohistochemical analyses of the peripheral and CNS tissues will be performed. These data will address whether declining cognition in aging mice is ameliorated by blocking innate immunity in microglia despite systemic metabolic syndrome. Data from these experiments will contribute to our knowledge of the systemic and CNS mechanisms by which metabolic syndrome-associated inflammation worsens cognitive function in aging individuals and will identify salient peripheral and CNS treatment targets.
Inflammation helps transform simple obesity into metabolic syndrome, including type 2 diabetes mellitus (T2DM), fatty liver, high cholesterol and atherosclerosis. Further, metabolic syndrome represents a risk factor for age-related dementias due in part to the associated inflammation. Our grant proposal focuses on how a key inflammatory signal operates in the brain or in the circulation, to promote age-related dementia in metabolic syndrome. We recently showed that selective deletion of this signal from a specific population of blood cells showed a remarkable effect: despite becoming obese on a high-fat diet, the mice were protected from metabolic syndrome in mice-they did not develop T2DM, fatty liver or atherosclerosis. We will study brain function in aging mice with metabolic syndrome to establish how quickly and how severely they lose memory function. We will then delete the inflammatory signal from specific inflammatory cells either throughout the entire mouse or only in the brain, to determine how reducing inflammation might protect memory function even in aged animals with obesity. Importantly, this particular inflammatory signal is found in the same form in humans as in mice, so our results may be applied to clinical drug trials without undue delay.
