LRP1 Activation Promotes Metabolic Reprogramming and Mrc1 Expression to Attenuate LPS-Induced Cognitive Deficits: An...

Area of Science:

• Neuroscience
• Metabolic research
• Immunology

Background:

• Central insulin resistance and neuroinflammation synergistically drive cognitive decline.
• Low-density lipoprotein receptor-related protein 1 (LRP1) maintains blood-brain barrier integrity but its role in decoupling the inflammation-metabolism axis is unclear.

Purpose of the Study:

• To investigate if LRP1 activation can ameliorate lipopolysaccharide (LPS)-induced cognitive deficits by recalibrating cerebral glucose metabolism.
• To explore the neuroprotective mechanisms of SP16, a selective LRP1 agonist.

Main Methods:

• Utilized behavioral phenotyping, targeted metabolomics, and transcriptomics in a mouse model.
• Induced cognitive dysfunction with intracerebroventricular (i.c.v) LPS administration.
• Administered SP16 intraperitoneally (i.p) to assess its effects.

Main Results:

• SP16 treatment preserved cognitive function and prevented neuronal atrophy in LPS-injected mice.
• LRP1 activation suppressed inflammation, modulated hippocampal insulin sensitivity, and restored redox homeostasis.
• Metabolomic profiling revealed restored glycolytic flux via normalization of fructose-1,6-bisphosphate (FBP) and upregulation of the M2-like marker Mrc1.

Conclusions:

• LRP1 regulates the link between metabolic health and immune resolution.
• SP16 induces a metabolic shift via the FBP node, promoting microglia from a pro-inflammatory to a reparative state.
• Targeting SP16-mediated metabolic reprogramming offers a therapeutic strategy for neuroinflammation-associated cognitive impairment.