Work

LRP1 Activation Promotes Metabolic Reprogramming and Mrc1 Expression to Attenuate LPS ‐Induced Cognitive Deficits: An Integrated Omics Analysis

Year: 2026

Type: article

Abstract: AIM: Central insulin resistance and neuroinflammation act as synergistic drivers in the pathogenesis of cognitive decline. While the low-density lipoprotein receptor-related protein 1 (LRP1) is known to maintain blood-brain barrier integrity, its capacity to decouple the inflammation-metabolism axis remains underexplored. This study investigates whether activation of LRP1 can ameliorate LPS-induced cognitive deficits by recalibrating cerebral glucose metabolism. METHODS: We utilized an integrative approach combining behavioral phenotyping with targeted metabolomics and transcriptomics to dissect the neuroprotective mechanism of SP16, a selective LRP1 agonist. Cognitive dysfunction was modeled in mice via intracerebroventricular (i.c.v) LPS administration, followed by systemic intervention with intraperitoneally (i.p) injected SP16. RESULTS: SP16 treatment preserved cognitive function and prevented neuronal structural atrophy against the LPS injection. Mechanistically, LRP1 activation did more than suppress inflammation; it functionally modulated hippocampal insulin sensitivity and re-established redox homeostasis. Crucially, metabolomic profiling highlighted a restoration of glycolytic flux, centered on the normalization of fructose-1,6-bisphosphate (FBP) levels. This metabolic reprogramming coincided with the upregulation of the M2-like reparative marker, Mrc1. CONCLUSION: Our findings identify LRP1 as a regulator that bridges metabolic health and immune resolution. By enforcing a metabolic shift via the FBP node, SP16 effectively guides microglia from a pro-inflammatory state toward tissue repair. Thus, honing in on SP16-mediated metabolic reprogramming presents an opportunity for a therapeutic intervention against neuroinflammation-associated cognitive impairment, offering a more nuanced alternative to broad-spectrum anti-inflammatories.

Source: CNS Neuroscience & Therapeutics

DOI: 10.1002/cns.70950