Synergistic Effects of Retromer Deficiency and High Fat Diet on Mouse Cognitive Function

Abstract

The retromer complex plays a critical role in endosome to trans‐Golgi retrieval of various transmembrane proteins. Vacuolar protein sorting‐associated protein 35 (VPS35), a critical component of the retromer cargo‐recognition subunit, has been implicated in neurodegenerative disease pathology. Our lab has previously shown that VPS35 deficiency exacerbates Alzheimer's Disease (AD) pathology in a mouse model of AD. As high fat diet consumption and metabolic syndrome are risk factors for neurodegenerative pathology and impaired cognitive function, we investigated if there is any synergistic effect between VPS35‐deficiency and dietary risk factors on AD‐relevant neuropathology. VPS35+/m mice were fed either standard control diet or high fat diet (HFD) for 12 weeks. Weight gain, fasting glucose, and glucose metabolism were measured weekly. VPS35 deficiency was found to alter glucose metabolism at an early age but to have no long‐term effect on glucose metabolism. HFD was found to extend the time frame of this effect by one week. To investigate synergistic effects on cognitive function, VPS35+/m mice were subjected to behavioral analysis following 10–12 weeks of control or HFD. A combined effect of VPS35 deficiency and HFD was observed in some, but not all, behavioral paradigms examined. Future studies will be necessary to identify the differential effects of VPS35 deficiency on cognitive function, which brain regions might most be affected by VPS35 deficiency following HFD, and the molecular nature of their synergistic effect.Support or Funding InformationSupport & funding provided by: Augusta University, Department of Neuroscience & Regenerative Medicine; Medical College of Georgia, Department of Neurology; National Institutes of Health National Institute on Aging; Charlie Norwood VA Medical Center