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.
Qu et al. (Fri,) studied this question.