Hexosamine Biosynthesis Pathway Is a Potential Link Between Insulin Resistance and Alzheimer’s Disease

Insulin resistance is associated with a high cumulative risk of AD and reduced cerebral glucose metabolism. New data suggest that increased hexosamine biosynthesis pathway (HBP) activity induces insulin resistance in adipose tissue and skeletal muscle via increased O-linked N-acetylglucosamine modification of Sp1, leading to transcriptional activation of HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. This HBP-induced cholesterolgenic transcriptional response in adipocytes and muscle cells increases cholesterol in the plasma membrane that impairs insulin-stimulated glucose transporter GLUT4-mediated glucose transport. A pilot, short-term (3-wk) high-fat (HF, 45% kCal) feeding study revealed that insulin-resistant mice trended to display early signs of cognitive dysfunction accompanied by apparent increases in cerebral, but not cerebellar, cholesterol. To extend those analyses and investigate whether a similar HBP response could contribute to excess cerebrum cholesterol, male and female C57BL/6 mice were placed on low-fat (LF, 10% kCal) or HF diets for 8 weeks. While HF-feeding induced impaired glucose tolerance in male and female mice, only male mice displayed impaired insulin tolerance. Strikingly, insulin-resistant male, but not insulin-sensitive female, mice displayed an increase in cerebral cholesterol (62.4%, p=0.02) with an apparent accompanying increase in cerebral, but not cerebellar, O-linked N-acetylglucosamine modification of Sp1. These preliminary data suggest that insulin resistance is associated with an increased cerebral HBP-induced cholesterolgenic transcriptional response that could impair cerebral glucose transport also mediated by GLUT4. Further molecular studies, glucose transport analyses, and cognitive/behavioral testing on this putative mechanism of AD are needed