Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

Pacific white shrimp (Litopenaeus vannamei) is the leading species farmed in the Western Hemisphere and an economically important aquaculture species in China. In this project, a genetic linkage map was constructed using amplified fragment length polymorphism (AFLP) and microsatellite markers. One hundred and eight select AFLP primer combinations and 30 polymorphic microsatellite markers produced 2071 markers that were polymorphic in either of the parents and segregated in the progeny. Of these segregating markers, 319 were mapped to 45 linkage groups of the female framework map, covering a total of 4134.4 cM; and 267 markers were assigned to 45 linkage groups of the male map, covering a total of 3220.9 cM. High recombination rates were found in both parental maps. A sex-linked microsatellite marker was mapped on the female map with 6.6 cM to sex and a LOD of 17.8, two other microsatellite markers were also linked with both 8.6 cM to sex and LOD score of 14.3 and 16.4. The genetic maps presented here will serve as a basis for the construction of a high-resolution genetic map, quantitative trait loci (QTLs) detection, marker-assisted selection (MAS) and comparative genome mapping.

‘Regulators of G protein Signalling’ (RGSs) accelerate the activation and deactivation kinetics of G protein‐gated inwardly rectifying K+ (GIRK) channels. In an apparent paradox, RGSs do not reduce steady‐state GIRK current amplitudes as expected from the accelerated rate of deactivation when reconstituted in Xenopus oocytes. We present evidence here that this kinetic anomaly is dependent on the degree of G protein‐coupled receptor (GPCR) precoupling, which varies with different Gαi/o‐RGS complexes. The gating properties of GIRK channels (Kir3.1/Kir3.2a) activated by muscarinic m2 receptors at varying levels of G protein expression were examined with or without the co‐expression of either RGS4 or RGS7 in Xenopus oocytes. Different levels of specific m2 receptor‐Gα coupling were established by uncoupling endogenous pertussis toxin (PTX)‐sensitive Gαi/o subunits with PTX, while expressing varying amounts of a single PTX‐insensitive subunit (Gαi1(C351G), Gαi2(C352G), Gαi3(C351G), GαoA(C351G), or GαoB(C351G)). Co‐expression of each of the PTX‐insensitive Gαi/o subunits rescued acetylcholine (ACh)‐elicited GIRK currents (IK,ACh) in a concentration‐dependent manner, with Gαo isoforms being more effective than Gαi isoforms. Receptor‐independent ‘basal’ GIRK currents (IK,basal) were reduced with increasing expression of PTX‐insensitive Gα subunits and were accompanied by a parallel rise in IK,ACh. These effects together are indicative of increased Gβγ scavenging by the expressed Gα subunit and the subsequent formation of functionally coupled m2 receptor‐G protein heterotrimers (Gα(GDP)βγ). Co‐expression of RGS4 accelerated all the PTX‐insensitive Gαi/o‐coupled GIRK currents to a similar extent, yet reduced IK,ACh amplitudes 60‐90 % under conditions of low Gαi/o coupling. Kinetic analysis indicated the RGS4‐dependent reduction in steady‐state GIRK current was fully explained by the accelerated deactivation rate. Thus kinetic inconsistencies associated with RGS4‐accelerated GIRK currents occur at a critical threshold of G protein coupling. In contrast to RGS4, RGS7 selectively accelerated Gαo‐coupled GIRK currents. Co‐expression of Gβ5, in addition to enhancing the kinetic effects of RGS7, caused a significant reduction (70‐85 %) in steady‐state GIRK currents indicating RGS7‐Gβ5 complexes disrupt Gαo coupling. Altogether these results provide further evidence for a GPCR‐Gαβγ‐GIRK signalling complex that is revealed by the modulatory affects of RGS proteins on GIRK channel gating. Our functional experiments demonstrate that the formation of this signalling complex is markedly dependent on the concentration and composition of G protein‐RGS complexes.