COBRE Pilot: Inhibition of Neural p38 as a Treatment for Obesity-induced Cognitive Dysfunction

One of the strongest modifiable risk factors for late-life dementia is midlife obesity. Though the incidence of Alzheimer’s disease has declined in recent years, the rising obesity prevalence threatens to undo much of this progress. While lifestyle interventions are important in preventing or delaying cognitive decline, such interventions are difficult to implement at scale and may not be entirely effective in reversing the pertinent central nervous system pathologies. High fat obesogenic diets are known to impair cognition in association with increased oxidative stress, neuroinflammation, cerebrovascular dysfunction, and synaptic loss. One promising therapeutic candidate in this regard is the stress-responsive kinase p38α, which is a major sensor of oxidative stress and regulator of inflammatory responses throughout the body. In the brain, its inhibition in various disease contexts directly ameliorates the types of pathologies caused by high fat diet. We therefore propose to test the central hypothesis that high fat diet induced obesity contributes to hippocampal dysfunction via activation of p38α and associated detrimental neuroinflammatory, vascular, and metabolic changes. We will do so in a single experiment designed to address two primary aims. Aim 1 will determine the persistent versus reversible effects of diet-induced obesity in the central nervous system. Aim 2 will assess whether inhibition of p38α rescues the pathology and cognitive dysfunction caused by high fat diet, either alone or in combination with a switch to healthy diet. These studies will use highly translational longitudinal neuroimaging and biomarker endpoints, as well as a p38α inhibitor currently in clinical trials for dementia (MW150), meaning that the results will be highly informative and relevant to public health regardless of outcome. In the process, we are setting the stage for a research program dedicated to expanding the pharmacopeia to enable precision-medicine approaches ultimately required to target the complex, multifactorial, and individualized pathological processes that contribute to Alzheimer’s dementia across the population.