LRPs in the Central Nervous System
The Neurobiology of Alzheimer's Disease Laboratory has uncovered several signaling pathways that are regulated by members of the low-density lipoprotein receptor (LDLR) family. These include the leptin and insulin signaling pathways regulated by LRP1 and the Wnt signaling pathway mediated by LRP6.
Using conditional gene deletion mouse models, the lab found that LRP1 regulates leptin signaling in the hypothalamus and mediates body energy homeostasis. Deletion of LRP1 in hypothalamic neurons resulted in an obese phenotype characterized by increased food intake, decreased energy consumption and decreased leptin signaling.
In a more recent study, Dr. Bu and his team found that LRP6-mediated Wnt signaling plays critical roles in supporting synaptic integrity and function. Deletion of LRP6 in forebrain neurons leads to age-dependent synaptic deficits and related memory impairments. Interestingly, LRP6-mediated Wnt signaling also regulates brain amyloid-beta metabolism. As LRP6-mediated Wnt signaling is compromised in Alzheimer's disease brains, restoring Wnt signaling holds promise as a new therapeutic strategy.
In addition, the lab showed that mice lacking LRP1 in forebrain neurons developed a global defect in brain lipid metabolism, characterized by decreased brain levels of cholesterol, sulfatide, galactosylceramide and triglyceride. These lipid deficits correlate with progressive, age-dependent dendritic spine degeneration, synapse loss, neuroinflammation, memory loss and eventual neurodegeneration.
The latest work from the lab has demonstrated that neuronal LRP1 regulates insulin signaling and glucose metabolism in the brain. The team found that deficiency of neuronal LRP1 leads to impaired insulin signaling and related impairments in cerebral glucose metabolism. As insulin signaling is compromised in Alzheimer's disease (AD) brains, these studies have strong implications in AD pathogenesis. This research also establishes LRP1 as a central metabolic receptor in the brain for both lipids and glucose.
Together, these studies show the critical role that LRP family members play in maintaining brain lipid and glucose homeostasis and associated synaptic and neuronal integrity. LRP1 and LRP6 are abundantly expressed in several cell types in the central nervous system, including glia and vascular cells, and neurons.
The lab's long-term goal is to define the mechanisms by which LRP family members and their ligands modulate brain metabolism and homeostasis. Several animal models are used in this research.