1,3‐Butanediol Mitigates High‐Salt Diet Induced Cognitive Impairment in Aging Mice

Abstract

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s disease (AD). Hypertension is the second leading risk factor for developing neurodegenerative disease. A recent study reported that Dietary salt promotes cognitive impairment through tau phosphorylation. However, the effect of ketone bodies or the precursor molecule (1,3‐butanediol) supplementation on cognitive impairment in aged mice or the absence of high salt has not been investigated. The study tests the hypothesis that 1,3‐butanediol attenuates the progression of vascular dementia mediated through histone acetylation mechanism in hypertensive aged mice. To test this hypothesis, we employed old male and female wild‐type (WT) mice. For three months, the mice were fed with a high salt diet (HSD) (8%). HSD mice have supplemented with ketone bodies precursor, 1,3‐Butanediol (2%), and ketone bodies compound β‐hydroxybutyrate (BHB, 0.2%) in drinking water for 12 weeks. Blood pressure was measured after 12 weeks of treatment by tail‐cuff plethysmography. After 12 weeks, urine and tissues were collected. The results show that 1,3‐Butanediol or BHB treatment reduced blood pressure and miRNA‐128‐3p in aged hypertensive mice. Further, the data analysis revealed the loss of short‐term and long‐term memory in HSD‐hypertensive mice compared to HSD+BHB or HSD+ 1,3‐Butanediol mice. This mechanistic study shows that HSD+ 1,3‐Butanediol mice display an increased mitochondrial TFAM dependent upregulation of brain‐derived neurotrophic factor (BDNF) and nuclear receptor subfamily 4A (Nr4a) in the mouse hippocampus via activation of the H3K27ac acetylation at the promoter. In addition, the anti‐miR‐128 treatment restored neuroprotective function and reduced the dementia pathology in old‐hypertensive mice. The present data demonstrate that 1,3‐Butanediol or BHB increases ketone bodies production and improves cognitive functions in aged hypertensive mice and could be a novel nutritional intervention for vascular dementia treatment.