| Title | Authors | Year |
|---|---|---|
| Inhibition of CGRP receptor ameliorates AD pathology by reprogramming lipid metabolism through HDAC11/LXRβ/ABCA1 signaling | Fan et al. | 2025 |
Overview
This study by Fan et al. (2025) reveals that blocking the calcitonin gene-related peptide (CGRP) receptor reverses Alzheimer’s pathology by reprogramming neuronal lipid metabolism. The receptor’s core subunit CALCRL was found to be elevated in the hippocampus of AD patients and 5×FAD mice. Inhibition using Rimegepant, a migraine drug, or genetic deletion of Calca, the gene encoding α-CGRP, reduced neurodegeneration, neuroinflammation, and behavioral deficits.
The work identifies a novel CALCRL–HDAC11–LXRβ–ABCA1 signaling pathway that shifts neurons away from oxidative injury and toward membrane repair. It connects excitatory stress signaling to lipid metabolic regulation and provides a mechanistic link between stress neurochemistry and energy homeostasis.
Mechanistic Sequence
-
Stress and CGRP receptor activation
- The CGRP receptor complex (CALCRL + RAMP1) becomes upregulated in response to stress and excitatory drive.
- CGRP activation increases intracellular calcium, ROS, and proinflammatory cytokines such as IL-1β and TNF-α.
-
Pharmacological inhibition
- Rimegepant (Rim), a small-molecule CGRP antagonist, reduced soluble Aβ1-42-induced neuronal death in vitro.
- It suppressed glial inflammation and improved neuronal viability after amyloid exposure.
-
Downstream pathway
- Inhibition of CGRP signaling suppresses HDAC11, a histone deacetylase that normally silences lipid homeostasis genes.
- Reduced HDAC11 activity increases LXRβ acetylation, enabling LXRβ to promote transcription of ABCA1, a key lipid efflux transporter.
- Enhanced ABCA1 expression drives cholesterol and phospholipid efflux, restoring lipid balance and protecting against peroxidation.
-
Outcomes in vivo
- In 5×FAD mice, chronic Rimegepant treatment improved spatial memory, reduced amyloid plaque deposition, mitigated tau hyperphosphorylation, and normalized hippocampal lipid metabolism.
- The effects were consistent across sexes and conserved in both human and mouse tissues.
Relevance to the Stress–Glutamate–ROS Model
The CGRP receptor is a stress-linked glutamatergic node distributed through the amygdala, periaqueductal gray, thalamus, and brainstem, overlapping with the Pedunculopontine–amygdala–spinal network. Its activation under stress mirrors the glutamate surge that triggers calcium-dependent ROS formation and mitochondrial overload.
By blocking this receptor, Rimegepant effectively interrupts the stress-to-excitotoxicity cascade, halting calcium-driven ROS generation. The subsequent suppression of HDAC11 promotes lipid repair and mitochondrial recovery.
This positions HDAC11 as a central repair switch in the aftermath of excitotoxic stress, analogous to flipping neurons from a damage phase into a metabolic restoration phase. The resulting lipid re-acetylation and ABCA1-mediated efflux restore membrane composition and reduce ferroptotic vulnerability.
Key Points
- CGRP receptor signaling is stress-responsive and contributes to excitotoxic neuroinflammation.
- Inhibiting this pathway via Rimegepant suppresses HDAC11 and restores LXRβ acetylation.
- LXRβ activation promotes ABCA1 expression, enhancing lipid and cholesterol turnover.
- The process rebalances neuronal membranes and counteracts oxidative lipid injury.
- This identifies HDAC11–LXRβ–ABCA1 as a lipid metabolic feedback loop following excitotoxic stress.
Broader Implications
This mechanism bridges migraine pharmacology with neurodegenerative disease therapeutics. It provides a biochemical map for how stress signaling and lipid repair converge, implying that targeting CGRP or HDAC11 could also protect against glutamate-driven neurodegeneration in conditions like ALS or Parkinson’s disease.
It also reinforces the concept that excitotoxic injury cannot be treated by receptor blockade alone. Recovery requires activation of lipid and mitochondrial repair systems. By identifying a single upstream receptor (CGRP) that controls both excitatory load and lipid reprogramming, this paper provides a powerful entry point for restoring neuronal homeostasis after chronic stress or calcium overload.
Reflection
CGRP inhibition represents more than symptom suppression. It serves as a metabolic reset, reversing the oxidative phase of stress through a defined molecular route. This pathway exemplifies how neuronal survival depends on the timely transition from excitation to repair, confirming a key prediction of the stress–glutamate–ROS model.