Inhibition of CGRP receptor ameliorates AD pathology by reprogramming lipid metabolism through HDAC11/LXRβ/ABCA1 signaling

SUMMARY The Calcitonin gene-related peptide (CGRP) receptor has gained attention in Alzheimer’s Disease (AD) research due to its involvement in regulating neuroinflammation. However, its role and mechanism in AD pathology remain unclear. Here, we demonstrate that CALCRL, a core component of the CGRP receptor, is upregulated in the hippocampus of AD dementia patients and 5×FAD mice. Knockout of the CGRP receptor ligand Calca or pharmacological blockade using Rimegepant (Rim), reduces soluble Aβ1-42 oligomer-induced neuronal death and glial inflammation. Rim treatment also rescues neurobehavioral impairments, neurodegeneration, and lipid metabolism dysfunction in 5×FAD mice. Mechanistically, these effects are mediated through HDAC11 inhibition, which enhances LXRβ acetylation and ABCA1 expression, promoting the reprogramming of neuronal lipid metabolism. Importantly, this CALCRL/HDAC11/LXRβ/ABCA1 axis is conserved across both humans and mice. Our findings uncover a novel mechanism underlying AD pathogenesis and highlight the therapeutic potential of targeting CGRP signaling in AD. HIGHLIGHTS Inhibition of CGRP receptor ameliorates disease pathology in models of AD HDAC11 mediates CGRP receptor function in AD HDAC11 is a pivotal regulator in lipid metabolism by LXRβ/ABCA1 signaling The HDAC11/LXRβ/ABCA1 axis is conserved in AD humans and mice