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

Abstract

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 GABAA receptor α1 levels and reduce β‐amyloid (Aβ) 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 β‐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 GABAA receptor α1 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 Aβ load in Alzheimer's disease.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer’s disease

“…Neuronal 40 Hz steady-state oscillations, evoked by daily optogenetic or sensory (visual and/or auditory) stimulation over several weeks have been shown to have multiple downstream biological effects, including attenuation of synaptic loss and neurodegeneration, reduction in amyloid and tau pathologies, and improvement in learning and memory in various AD mouse models (10)(11)(12)(13)(14). These original findings have been confirmed and extended by numerous subsequent publications (15)(16)(17)(18), although not by all (19,20).…”

A paradoxical switch: the implications of excitatory GABAergic signaling in neurological disorders

“…Imbalances between NKCC1 and KCC2 have recently been shown in patients with AD ( 77 , 78 ) that are exacerbated with the onset of epileptic activity, indicating that hyperexcitability can act as a feed-forward mechanism to promote excitatory GABAergic signaling. Previous findings in preclinical models of amyloid-beta deposition (APP/PS1 transgenic mice and Aβ 1-40 fibril treatment) note reduced KCC2 protein expression in the hippocampus and cortex ( 71 , 76 , 79 , 80 ) with increases in NKCC1 protein expression ( 81 ). One study, however, indicates increases in KCC2 in a different model of AD-related pathology.…”

White Light Stimulation at Gamma Frequency to Modify the Aβ42 and tau Proteins in SH-SY5Y Cells

“… 23 Additionally, 40 Hz gamma frequency light flickering may enhance KCC2 expression and PKC-dependent phosphorylation of APP on a serine residue. 28 This could enhance APP trafficking to the plasma membrane, thereby reducing the Aβ load in AD. In brief, the white light stimulation at gamma frequency may exert a more pronounced effect on Aβ42 levels, possibly via modulating KCC2 expression and APP trafficking to the plasma membrane.…”