SQSTM1/ p62 oligomerization contributes to Aß-induced inhibition of Nrf2 signaling.

SQSTM1/p62, also known as sequestosome 1 (SQSTM1) or p62, is an intracellular protein induced by stress and functions as an adaptor molecule in diverse cellular processes. Oxidative damage induced by overproduction of amyloid-ß (Aß) and the impairment of endogenous antioxidant Nrf2 signaling have been documented in the brains of Alzheimer's disease (AD) patients. The causes of the inactivation of Nrf2 signaling under Aß-induced oxidative stress are unclear, and p62 might be involved in this process. In this study, APP/PS1 transgenic mice, Aß intrahippocampal injection rat model, and SH-SY5Y cells were used to reveal that the alterations in the oligomeric state of p62 participated in the regulation of Nrf2 signaling under Aß insult. The present in vivo and in vitro studies revealed that short-term treatment of Aß activated Nrf2 signaling, while long-term Aß treatment inhibited it through either canonical or noncanonical Nrf2 activation pathway. p62 oligomerization was largely attenuated under long-term Aß treatment. The reduction of p62 oligomerization weakened p62 sequestration to Keap1, leading to Nrf2 signaling inhibition. Our findings provide a better understanding of p62-mediated modulation on Nrf2 activity and highlight a potential therapeutic target of p62 in AD.

S-Adenosylmethionine Alleviates Amyloid-ß-Induced Neural Injury by Enhancing Trans-Sulfuration Pathway Activity in Astrocytes.

BACKGROUND: Glutathione (GSH) is an important endogenous antioxidant protecting cells from oxidative injury. Cysteine (Cys), the substrate limiting the production of GSH, is mainly generated from the trans-sulfuration pathway. S-adenosylmethionine (SAM) is a critical molecule produced in the methionine cycle and can be utilized by the trans-sulfuration pathway. Reductions in GSH and SAM as well as dysfunction in the trans-sulfuration pathway have been documented in the brains of Alzheimer's disease (AD) patients. Our previous in vivo study revealed that SAM administration attenuated oxidative stress induced by amyloid-ß (Aß) through the enhancement of GSH. OBJECTIVE: To investigate the effect of Aß-induced oxidative stress on the trans-sulfuration pathway in astrocytes and neurons, respectively, and the protective effect of SAM on neurons. METHODS: APP/PS1 transgenic mice and the primary cultured astrocytes, neurons, and HT22 cells were used in the current study. RESULTS: SAM could rescue the low trans-sulfuration pathway activity induced by Aß only in astrocytes, accompanying with increasing levels of Cys and GSH. The decrease of cellular viability of neurons caused by Aß was greatly reversed when co-cultured with astrocytes with SAM intervention. Meanwhile, SAM improved cognitive performance in APP/PS1 mice. CONCLUSION: In terms of astrocyte protection from oxidative stress, SAM might be a potent antioxidant in the therapy of AD patients.

Responsive Expression of MafF to ß-Amyloid-Induced Oxidative Stress.

The small musculoaponeurotic fibrosarcoma (sMaf) proteins MafF, MafG, and MafK are basic region leucine zipper- (bZIP-) type transcription factors and display tissue- or stimulus-specific expression patterns. As the oxidative stress reactive proteins, sMafs are implicated in various neurological disorders. In the present study, the expressions of sMafs were investigated across five databases gathering transcriptomic data from 74 Alzheimer's disease (AD) patients and 66 controls in the Gene Expression Omnibus (GEO) database. The expression of MafF was increased in the hippocampus of AD patients, which was negatively correlated with the expression of the glutamate cysteine ligase catalytic subunit (GCLC). Furthermore, MafF was significantly increased in patients with Braak stage V-VI, compared to those with Braak stage III-IV. ß-Amyloid (Aß), a strong inducer of oxidative stress, plays a crucial role in the pathogenesis of AD. The responsive expressions of sMafs to Aß-induced oxidative stress were studied in the APP/PS1 mouse model of AD, Aß intrahippocampal injection rats, and several human cell lines from different tissue origins. This study revealed that only the induction of MafF was accompanied with reduction of GCLC and glutathione (GSH). MafF knockdown suppressed the increase of GSH induced by Aß. Among sMafs, MafF is the most responsive to Aß-induced oxidative stress and might potentiate the inhibition of antioxidation. These results provide a better understanding of sMaf modulation in AD and highlight MafF as a potential therapeutic target in AD.