LRP1 in the Central Nervous System

Recently, Dr. Bu's laboratory has uncovered a new molecular pathway in which low-density lipoprotein receptor-related protein 1 (LRP1) regulates leptin signaling and energy homeostasis. Deletion of LRP1 in forebrain neurons resulted in an obese phenotype characterized by increased food intake, decreased energy consumption and decreased leptin signaling.1

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.

Illustration of LRP1 and mice

The lab further demonstrated that the levels of glutamate receptor subunits N-methyl-d-aspartate (NMDA) receptor 1 and glutamate receptor 1 are selectively reduced in LRP1 forebrain knockout mice and in LRP1 knockdown neurons, which are partially rescued by restoring neuronal cholesterol.2

Together, these studies show the critical role that LRP1 plays in maintaining brain lipid homeostasis and associated synaptic and neuronal integrity. LRP1 is abundantly expressed in several cell types in the central nervous system, including glia and vascular cells, and neurons.

The lab's long-term goal related to this research focus is to define the mechanisms by which LRP1 and its ligands modulate brain cholesterol metabolism and brain homeostasis. Several animal models are used in this research.

References

  • Liu Q, Zhang J, Zerbinatti C, Zhan Y, Kolber BJ, Herz J, Muglia LJ, Bu G. Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system. PLoS Biol. 2011 Jan 11;9(1):e1000575. PMID: 21264353
  • Liu Q, Trotter J, Zhang J, Peters MM, Cheng H, Bao J, Han X, Weeber EJ, Bu G. Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J Neurosci. 2010 Dec 15;30(50):17068-78. PMID: 21159977