Photobiomodulation suppresses JNK3 by activation of ERK/MKP7 to attenuate AMPA receptor endocytosis in Alzheimer's disease

Abstract

Alzheimer's disease (AD), a severe age‐related neurodegenerative disorder, lacks effective therapeutic methods at present. Physical approaches such as gamma frequency light flicker that can effectively reduce amyloid load have been reported recently. Our previous research showed that a physical method named photobiomodulation (PBM) therapy rescues Aβ‐induced dendritic atrophy in vitro. However, it remains to be further investigated the mechanism by which PBM affects AD‐related multiple pathological features to improve learning and memory deficits. Here, we found that PBM attenuated Aβ‐induced synaptic dysfunction and neuronal death through MKP7‐dependent suppression of JNK3, a brain‐specific JNK isoform related to neurodegeneration. The results showed PBM‐attenuated amyloid load, AMPA receptor endocytosis, dendrite injury, and inflammatory responses, thereby rescuing memory deficits in APP/PS1 mice. We noted JNK3 phosphorylation was dramatically decreased after PBM treatment in vivo and in vitro. Mechanistically, PBM activated ERK, which subsequently phosphorylated and stabilized MKP7, resulting in JNK3 inactivation. Furthermore, activation of ERK/MKP7 signaling by PBM increased the level of AMPA receptor subunit GluR 1 phosphorylation and attenuated AMPA receptor endocytosis in an AD pathological model. Collectively, these data demonstrated that PBM has potential therapeutic value in reducing multiple pathological features associated with AD, which is achieved by regulating JNK3, thus providing a noninvasive, and drug‐free therapeutic strategy to impede AD progression.

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

“…Western blot analysis and co‐immunoprecipitation (co‐IP) were performed following previous description with some modification (Bourdenx et al, 2021; Shen et al, 2021; Zhang et al, 2021). We performed plasma membrane protein isolation according to the directions provided by Minute™ Plasma Membrane Protein Isolation and Cell Fractionation Kit (Invent Biotechnologies, catalog number: SM‐005).…”

Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease

“…Moreover, reduced function of CaMKII, a fundamental signaling protein in LTP, is also implicated (Gu et al, 2009; see also Ghosh & Giese, 2015). Although the mechanisms responsible for the decline in AMPAR number and surface expression are varied and complex, it is likely that an impairment in intracellular endocytic recycling and increased AMPAR endocytosis at synaptic sites has a critical role (Shen et al, 2021; Xian et al, 2018; Zhao et al, 2010). Other evidence suggests that increased internalization of AMPARs stimulated by Aβ accumulation is due to enhanced ubiquitination of receptors followed by their degradation (Guntupalli et al, 2017; Rodrigues et al, 2016; Zhang, Guo, et al, 2018).…”

Transcranial near-infrared light in treatment of neurodegenerative diseases

“…The study revealed potential therapeutic value by achieving regulation of the JNK3 kinase pathway and stabilizing the MKP7 cascade, which is believed to be brain-specific isoforms associated with neurodegeneration cascades. Observed molecular changes translated into the rescue of memory loss deficit, amyloid load reduction, synaptic loss, and neuroinflammation in AD model transgenic APP/PS1 mice treated with PBM ( Shen et al, 2021 ). The beneficial findings observed in AD model animal studies draw more attention and build an evidence-based foundation in the biomedical community to make more clinical trials.…”