Ml muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2′,5′‐dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K‐Akt signaling induced by M1 receptor activation could be abolished by cAMP‐PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K‐Akt, by short‐term application of rapamycin attenuated the effects of Ml receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP‐PKA and PI3K‐Akt‐mTOR pathways but is irrelevant to protein synthesis.—Zhao, L.‐X., Ge, Y.‐H., Li, J.‐B., Xiong, C.‐H., Law, P.‐Y., Xu, J.‐R., Qiu, Y., Chen, H.‐Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP‐PKA and PI3K‐Akt. FASEB J. 33, 6622–6631 (2019). http://www.fasebj.org

Background Ribosomal protein S6 kinase 1 (S6K1) is a serine–threonine kinase that has two main isoforms: p70S6K (70-kDa isoform) and p85S6K (85-kDa isoform). p70S6K, with its upstream mammalian target of rapamycin (mTOR), has been shown to be involved in learning and memory and participate in the pathophysiology of Alzheimer’s disease (AD). However, the function of p85S6K has long been neglected due to its high similarity to p70S6k. The role of p85S6K in learning and memory is still largely unknown. Methods We fractionated the postsynaptic densities to illustrate the differential distribution of p85S6K and p70S6K. Coimmunoprecipitation was performed to unveil interactions between p85S6K and the GluA1 subunit of AMPA receptor. The roles of p85S6K in synaptic targeting of GluA1 and learning and memory were evaluated by specific knockdown or overexpression of p85S6K followed by a broad range of methodologies including immunofluorescence, Western blot, in situ proximity ligation assay, morphological staining and behavioral examination. Further, the expression level of p85S6K was measured in brains from AD patients and AD model mice. Results p85S6K, but not p70S6K, was enriched in the postsynaptic densities. Moreover, knockdown of p85S6K resulted in defective spatial and recognition memory. In addition, p85S6K could interact with the GluA1 subunit of AMPA receptor through synapse-associated protein 97 and A-kinase anchoring protein 79/150. Mechanistic studies demonstrated that p85S6K could directly phosphorylate GluA1 at Ser845 and increase the amount of GluA1 in synapses, thus sustaining synaptic function and spine densities. Moreover, p85S6K was found to be specifically decreased in the synaptosomal compartment in the brains of AD patients and AD mice. Overexpression of p85S6K ameliorated the synaptic deficits and cognitive impairment in transgenic AD model mice. Conclusions These results strongly imply a significant role for p85S6K in maintaining synaptic and cognitive function by interacting with GluA1. The findings provide an insight into the rational targeting of p85S6K as a therapeutic potential for AD.

ScopeThe effect of α‐mangostin (α‐M), a polyphenolic xanthone isolated from mangostin, on lipopolysaccharide (LPS)‐induced microglial activation and memory impairment is explored. The possible underlying mechanisms are also investigated.Methods and ResultsCytokine production and activation of transforming growth factor activated kinase‐1 (TAK1) and nuclear factor‐κB (NF‐κB) are detected by enzyme‐linked immunosorbent assay (ELISA) or Western blot. Microglial migration and phagocytosis are evaluated with scratch wound‐healing assay and phagocytosis of fluorescent latex beads, respectively. Learning and memory abilities of mice are evaluated with the Morris water maze test. The nanomolar (100–500 nm) α‐M suppresses LPS‐induced pro‐inflammatory cytokine production and inducible nitric oxide synthase (iNOS) expression in microglia. It also inhibits LPS‐induced microglial migration and phagocytosis. α‐M rescues LPS‐caused, microglia‐mediated neuronal dendritic damage. Moreover, α‐M represses LPS‐induced toll‐like receptor 4 (TLR4) expression and activation of TAK1 and NF‐κB. In a mouse neuroinflammation model, α‐M (50 mg kg−1 day−1) shows obvious anti‐neuroinflammatory, neuroprotective, and memory‐improving effects in vivo.Conclusionα‐M inhibits microglia‐mediated neuroinflammation and prevents neurotoxicity and memory impairment from inflammatory damage. These results indicate that α‐M has great potential to be used as a nutritional preventive strategy for neuroinflammation‐related neurodegenerative disorders such as Alzheimer's disease.

Selenium (Se) is essential for the basic functions of life, but the low daily intake of Se urges us to find reliable ways to increase food Se content. Plant-growth-promoting bacteria (PGPB) have shown potential in enhancing plant growth and Se accumulation. In this study, the soils collected from a Se tailing were used to isolate Se-tolerant PGPB. The results showed that a total of three strains were identified. Strain LWS1, belonging to Priestia sp., grew well in M9 medium and exhibited typical PGP characteristics by an IAA-production ability of 24.3 ± 1.37 mg·L−1, siderophore-production ability of 0.23 ± 0.04 and phosphate-solubilizing ability of 87.5 ± 0.21 mg·L−1. Moreover, LWS1 strain tolerated selenite (SeIV) up to 90 mM by a LC50 of 270.4 mg·L–1. Further investigations demonstrated that the inoculation of strain LWS1 resulted in up to 19% higher biomass and 75% higher Se concentration in rice (Oryza sativa L.) than uninoculated treatments. Our study has provided evidence that microbial Se biofortification through inoculating with Priestia sp. strain LWS1 is an alternative way to improve Se uptake in crops and maintain human health.