Obesity accelerates age-related memory deficits and alters white matter tract integrity in Ldlr-/-.Leiden mice

- Background: Obesity in mid-adulthood has been suggested to promote brain aging and is associated with progressive cognitive impairment later in life. However, the structural and functional alterations that underlie obesity-related cognitive dysfunction are still poorly understood, partly owing to the lack of translational models replicating age- and obesity-related brain pathology. - Methods: The effect of age and high-fat diet (HFD)-induced obesity was investigated in adult Ldlr-/-.Leiden mice, an established translational model for obesity and its comorbidities. During mid-adulthood, from three to eight months of age, brain structure and function (hippocampal volume, cortical thickness, white matter integrity, cerebral blood flow (CBF), resting-state functional connectivity) were monitored with brain magnetic resonance imaging, and cognitive function was evaluated using cognitive tests. Brain pathology was further examined with histopathological and gene expression analyses. - Results: Ldlr-/-.Leiden mice showed age-related decreases in cortical thickness, CBF, brain connectivity, and neurogenesis along with the development of neuroinflammation and (short-term) memory impairments. On HFD feeding, Ldlr-/-.Leiden mice exhibited similar features, but memory deficits started at a younger age than in chow-fed mice. HFD-fed mice additionally showed a rise in CBF with concomitant decline in fractional anisotropy in white matter tracts. Analyses of hippocampal gene expression further revealed an age-related suppression of processes related to metabolic and neuronal function while HFD feeding strongly activated neuroinflammatory pathways. - Conclusions: Ldlr-/-.Leiden mice show similar critical age-related changes in brain structure and function as observed in humans. In this mouse model, HFD feeding particularly trigger disturbances in brain blood perfusion and white matter tract integrity, which may underlie an accelerated cognitive decline in obesity. At the start of the experiment the animals were 10-12 weeks old (corresponding to young adults). One group of chow-fed mice (Young-Chow, n=15) was euthanized at 3 months of age as a younger lean (healthy) reference. Then, from 2.5 to 8 months of age, one aging group (Aging-Chow, n=15) remained on the standardized chow diet and another aging group (HFD, n=17) was fed an obesity-inducing energy-dense high-fat diet (HFD). These 2 groups were sacrificed around 8 months of age. RNAseq analysis was performed on Hippocampi isolated from the right hemispheres of fresh brains at sacrifice.