Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing beta-amyloid load in Alzheimer's disease model

Inducing gamma oscillations with non-invasive light flicker has been reported to impact Alzheimer's disease-related pathology. However, it is unclear which signaling pathways are involved in reducing amyloid load. Here, we found that gamma frequency light flicker increased anchoring of amyloid precursor protein (APP) to the plasma membrane for non-amyloidogenic processing, and then physically interacted with KCC2, a neuron-specific K+-Cl- cotransporter, suggesting that it is essential to maintain surface GABA(A) receptor alpha 1 levels and reduce beta-amyloid (A beta) production. Stimulation with such light flicker limited KCC2 internalization and subsequent degradation via both tyrosine phosphorylation and ubiquitination, leading to an increase in surface-KCC2 levels. Specifically, PKC-dependent phosphorylation of APP on a serine residue was induced by gamma frequency light flicker, which was responsible for maintaining plasma membrane levels of full-length APP, leading to its reduced trafficking to endosomes and inhibiting the beta-secretase cleavage pathway. The activated PKC from the gamma frequency light flicker subsequently phosphorylated serine of KCC2 and stabilized it onto the cell surface, which contributed to the upregulation of surface GABA(A) receptor alpha 1 levels. Together, these data indicate that enhancement of APP trafficking to the plasma membrane via light flicker plays a critical modulatory role in reduction of A beta load in Alzheimer's disease.