Transcranial photobiomodulation induced frequency-specific dual-pathway glial activation for neurovascular protection vs amyloid clearance in Alzheimer’s disease

Vascular network impairment is a critical driver of Alzheimer’s Disease (AD) progression, yet strategies to effectively regulate vascular pathology remain unclear. Here, we attempted to employ transcranial continuous-wave (CW) and 40Hz near-infrared (NIR) light stimulation to target vascular network in 5xFAD mice. The results showed that NIR light significantly ameliorated cognitive dysfunction via enhancing β-amyloid (Aβ) plaque clearance and providing neurovascular protection. Glial cell activation served as the primary mediator through which NIR light achieved these modulation effects. The colocalization and correlational analyses revealed that CW-NIR light primarily activated astrocyte-vascular synergism to ameliorate vascular dysfunction, thereby conferring synaptic protection. In contrast, 40Hz light primarily activated microglia to increase their aggregation around Aβ plaque, which enhanced Aβ local clearance. These differential mediating pathways suggested that CW and 40Hz exhibited modality-specific therapeutic advantages for distinct AD pathological hallmarks – vascular dysfunction and Aβ plaque deposition, respectively. These findings potentially offer a precision light stimulation strategy targeting different neurodegenerative hallmarks.