There is a dire need to discover new targets for Alzheimer's disease (AD) drug development. Decreased neuronal glucose metabolism that occurs in AD brain could play a central role in disease progression. Little is known about the compensatory neuronal changes that occur to attempt to maintain energy homeostasis. In this review using the PubMed literature database, we summarize evidence that amino acid oxidation can temporarily compensate for the decreased glucose metabolism, but eventually altered amino acid and amino acid catabolite levels likely lead to toxicities contributing to AD progression. Because amino acids are involved in so many cellular metabolic and signaling pathways, the effects of altered amino acid metabolism in AD brain are far-reaching. Possible pathological results from changes in the levels of several important amino acids are discussed. Urea cycle function may be induced in endothelial cells of AD patient brains, possibly to remove excess ammonia produced from increased amino acid catabolism. Studying AD from a metabolic perspective provides new insights into AD pathogenesis and may lead to the discovery of dietary metabolite supplements that can partially compensate for alterations of enzymatic function to delay AD or alleviate some of the suffering caused by the disease.

SummaryT cells play a pivotal role in controlling viral infection; however, the precise mechanisms responsible for regulating T-cell differentiation and function during infections are incompletely understood. In this study, we demonstrated an expansion of myeloid-derived suppressor cells (

Co-infection of hepatitis B virus (HBV) with hepatitis C virus (HCV) is quite common, leading to an increase in morbidity and mortality. As such, HBV vaccination is recommended in HCV-infected individuals. HBV vaccine responses in HCV-infected individuals, however, are often blunted when compared to uninfected populations. The mechanism for this failure of vaccine response in HCV-infected subjects remains unclear. In this study, we investigated the expression and function of an inhibitory receptor, killer cell lectin-like receptor subfamily G member 1 (KLRG1), in regulation of CD4+ T cells and HBV vaccine responses during HCV infection. We demonstrated that KLRG1 was over-expressed on CD4+ T cells from HCV-infected, HBV vaccine non-responders (HBV-NR) compared to those responders (HBV-R). The capacity of CD4+ T cell to proliferate and secrete IL-2 cytokine was inversely associated with the level of KLRG1 expression. Importantly, blocking KLRG1 signaling resulted in a significant improvement of CD4+ T cell proliferation and IL-2 production in HCV-infected, HBV-NR in response to T cell receptor (TCR) stimulation. Moreover, blockade of KLRG1 increased the phosphorylation of Akt (Ser473) and decreased the expression of cell cycle inhibitors p16ink4a and p27kip1, which subsequently enhanced CDK 2 and cyclin E expressions. These results suggest that the KLRG1 pathway impairs CD4+ T cell responses to neo-antigen and induces a state of immune senescence in individuals with HCV infection, raising the possibility that blocking this negative signaling pathway might improve HBV vaccine responses in the setting of chronic viral infection.

T cells play a crucial role for viral clearance or persistence; however, the precise mechanisms that control their responses during viral infection remain incompletely understood. microRNAs (miR) have been implicated as key regulators controlling diverse biological processes through posttranscriptional repression. Here, we demonstrate that hepatitis C virus (HCV)-mediated decline of miR-181a expression impairs CD4+ T cell responses via over-expression of dual specific phosphatase 6 (DUSP6). Specifically, a significant decline of miR-181a expression along with over-expression of DUSP6 were observed in CD4+ T cells from chronically HCV-infected individuals compared to healthy subjects, and the levels of miR-181a loss were found to be negatively associated with the levels of DUSP6 over-expression in these cells. Importantly, reconstitution of miR-181a or blockade of DUSP6 expression in CD4+ T cells led to improved T cell responses including enhanced CD25 and CD69 expressions, increased IL-2 expression, and improved proliferation of CD4+ T cells derived from chronically HCV-infected individuals. Since a decline of miR-181a concomitant with DUSP6 over-expression are the signature markers for age-associated T cell senescence, these findings provide novel mechanistic insights into HCV-mediated premature T cell aging via miR-181a-regulated DUSP6 signaling, and reveal new targets for therapeutic rejuvenation of impaired T cell responses during chronic viral infection.

Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer's disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.