Magnetoreceptors in Alzheimer’s disease

AD is a progressive neurodegenerative disorder characterized by synaptic dysfunction, cognitive decline, and selective neuronal vulnerability in the hippocampus and cortex. While extracellular Aβ plaques and intracellular NFTs composed of hyperphosphorylated tau define AD pathology, accumulating evidence highlights mitochondrial dysfunction, oxidative stress, impaired proteostasis, neuroinflammation, and circadian dysregulation as convergent drivers of disease progression. In this context, emerging studies suggest that magnetoreceptors, particularly CRY/MagR complexes, may influence neuronal redox homeostasis, mitochondrial metabolism, synaptic function, and circadian timing, providing a potential mechanistic interface between magnetic field sensitivity and neurodegenerative processes [94-96].

CRY/MagR complexes operate through radical-pair chemistry, generating spin-correlated electrons within FAD and adjacent aromatic residues. Perturbations in radical-pair dynamics can modulate intracellular redox signalling and ROS production. In metabolically active cortical and hippocampal neurons, even modest elevations in ROS can exacerbate mitochondrial electron leakage, disrupt cardiolipin integrity and impair ATP synthesis, amplifying oxidative stress and calcium dysregulation. Redox-sensitive calcium channels, including voltage-gated calcium channels and the mitochondrial calcium uniporter, may further couple oxidative stress to intracellular calcium overload, promoting activation of proteases and kinases implicated in AD pathology [97-99].

Oxidative modifications of Aβ, including methionine oxidation and tyrosine cross-linking, enhance β-sheet formation and oligomer stability, while redox-dependent modulation of β- and γ-secretase activity can bias APP processing toward the amyloidogenic pathway. Similarly, tau phosphorylation is highly sensitive to oxidative stress, as ROS-activated kinases including GSK3β, CDK5, and stress-activated MAPKs promote tau hyperphosphorylation, whereas oxidative inhibition of phosphatases such as PP2A prolongs pathological tau states. These mechanisms favour tau misfolding, paired helical filament formation, and NFTs accumulation [100-102].

Beyond protein aggregation, radical-pair-induced redox perturbations can compromise neuronal proteostasis. Oxidative damage to molecular chaperones, autophagy regulators, and lysosomal enzymes impairs the clearance of misfolded Aβ and tau, reinforcing a feed-forward loop of mitochondrial dysfunction and proteostasis failure. At the network level, ROS-sensitive ion channels and redox-modulated signalling pathways can alter neuronal excitability, synaptic plasticity, and long-term potentiation, providing a mechanistic link between magnetic field-dependent radical-pair signalling and synaptic dysfunction in AD [103-105].

CRYs are also core components of the molecular circadian clock. CRY-dependent circadian regulation orchestrates neuronal metabolism, mitochondrial dynamics, antioxidant defences, and synaptic homeostasis in a time-of-day-dependent manner. Disruption of CRY oscillations can impair sleep-wake cycles, reduce slow-wave sleep, and desynchronize neuronal and glial populations. Circadian dysfunction has been strongly associated with impaired glymphatic clearance of metabolic waste, including Aβ, primarily during sleep. Altered circadian control of kinase and phosphatase activity may bias tau toward hyperphosphorylation, while circadian disruption of autophagy and lysosomal pathways further impairs proteostasis. These observations suggest that circadian misalignment and radical-pair-dependent redox perturbations are interconnected mechanisms that converge on neuronal vulnerability in AD [95,106].

Importantly, emerging evidence indicates that external magnetic fields can modulate CRY activity, providing a potential means to influence CRY/MagR signalling in neural tissue. In Drosophila, exposure to moderate static magnetic fields (~100 mT) potentiates blue-light-activated CRY signalling, resulting in enhanced neuronal depolarization and increased action potential firing in a CRY-dependent manner. Additionally, field strengths slightly above the ambient GMF (e.g. 500 μT) have been shown to influence the phosphorylation state and conformational activity of CRY1 and CRY2 proteins, modifying their photoreceptive output. Behavioural studies indicate that alternating or static magnetic fields can also modulate memory formation, learning, and neural excitability in a CRY-dependent fashion, highlighting a mechanistic link between magnetoreception and neural circuit function [78,90,107].

While direct causal evidence in mammalian neurons or human AD models remains limited, these findings suggest that external magnetic fields could modulate CRY-mediated radical-pair signalling, redox homeostasis, mitochondrial metabolism, synaptic plasticity, and circadian regulation processes central to AD pathology. Conceptually, magnetic field modulation of CRY/MagR activity could influence oxidative stress, Aβ clearance, tau phosphorylation, and synaptic function, providing a non-invasive approach to probe or potentially alter neurodegenerative pathways. Further studies in mammalian and human-relevant models are required to determine whether these effects are physiologically significant and therapeutically actionable [108,109].