Long term high‐fat feeding induces cognitive impairment, alterations in microglial morphology, and spatial transcriptomic changes

Abstract

AbstractBackgroundObesity and metabolic dysfunction (Metabolic Syndrome, prediabetes, and diabetes) increase the risk of later life cognitive impairment, including dementias such as Alzheimer’s Disease1‐3. One common etiology that might underly this increased risk is immune system dysregulation and inflammation4, 5. Specifically, microglial dependent mechanisms are thought to play an important role in pathology6‐8. However, the precise immune and inflammatory mechanisms promoting cognitive decline secondary to obesity and metabolic dysfunction are unclear.MethodBL6 male mice were fed 60% HFD (high fat diet) or 10% SD (standard diet) for 1 year. Body weight and glucose tolerance were assessed longitudinally. Cognition was repeatedly evaluated using Morris water maze, social recognition, and puzzle box. At study termination, mice were given either an intraperitoneal injection of lipopolysaccharide as an immune challenge or saline as a control. Activation of hippocampal microglia was assessed via immunohistochemistry (IHC) and analysis of microglial morphology. Changes in brain gene expression were measured via spatial transcriptomics using the 10X Visium platform.ResultHFD feeding caused increased weight, impaired glucose tolerance, and cognitive deficits which persisted throughout the study period. Body weight in particular was predictive of cognitive changes, especially for later time points. In response to immune challenge, hippocampal microglia in SD mice had a normal morphological response indicative of activation. However, microglia of HFD mice had no change in their morphology in response to lipopolysaccharide injection. Additionally, changes in morphology significantly correlated with cognition and indicated that a higher percentage of activated hippocampal microglia is associated with a worse cognitive phenotype. Spatial transcriptomics analysis showed changes in gene expression in multiple brain regions of HFD mice, including the hippocampus, many of which were related to neurodegenerative and inflammatory pathways.ConclusionThese data support that HFD feeding causes an early and persistent cognitive impairment, which is associated with obesity. Our data also confirm a role for microglia in HFD‐induced cognitive impairment. Indeed, microglial and transcriptomic data strongly indicate a role for inflammation and inflammatory pathways in HFD‐induced cognitive impairment.