The other end of APP

Investigators at Stanford University have created a panel of isogenic iPSC-derived neurons with various mutations of amyloid precursor protein (APP) and presenilin (PSEN), and used it to demonstrate that accumulation of APP beta C-terminal fragments (beta-CTFs), but not of amyloid beta, correlated with endosomal dysfunction and could be improved by inhibiting beta-secretase (BACE-1). Genetic evidence clearly implicates APP misprocessing in Alzheimer's disease (AD), and amyloid beta plaques are the disease's major anatomical calling card, which has led to a focus on therapeutic targeting of the latter. However, that therapeutic targeting has failed multiple times, and the evidence linking amyloid beta to AD is weaker than that for APP. Recently, endosomal dysfunction has been proposed as "another plausible underlying pathological mechanism," leading the authors to investigate the causes of endosomal dysfunction in their cell lines. They showed that endosomal dysfunction, which leads to deficits in intracellular transport, was correlated with changes in beta-CTF but not amyloid beta. The team acknowledged that amyloid beta could be causing neuronal damage via other mechanisms, but concluded that "our study raises the concern that [gamma secretase modulators] and other anti-Abeta therapies that are being developed and tested in the clinic all fail to target beta-CTF and, therefore, may have no effect on rescuing endosomal abnormalities in AD.... Although future studies are necessary to understand the precise pathway through which beta-CTF results in early endosome enlargement and dysregulation, interventions targeting this pathway deserve consideration as a therapeutic strategy." They published their results in the Aug. 12, 2019, issue of Neuron.

Muscle-produced BDNF controls metabolic switch in females

BDNF may stand for brain-derived neurotrophic factor, but researchers at Hong Kong University have demonstrated that it was also produced by muscles in response to fasting, and that its production and effects differed between male and female mice. Muscle can generate energy either from glucose via glycolysis or from lipids via fatty acid oxidation, and when energy demand is high in relation to supply, muscles will switch to fatty acid oxidation to preserve glucose for organs such as the brain that rely on glucose. However, what drives the switch has not been clear at the molecular level. The authors showed that female, but not male, mice whose muscles were unable to produce BDNF could not switch to fatty acid oxidation during fasting. "These mutant mice displayed myofiber necrosis, weaker muscle strength, reduced locomotion, and muscle-specific insulin resistance," the authors wrote, adding that "our results show that muscle-derived BDNF facilitates metabolic adaption during nutrient scarcity in a gender-specific manner and that insufficient BDNF production in skeletal muscle promotes the development of metabolic myopathies and insulin resistance." Their work appeared in the Aug. 13, 2019, issue of Science Signaling.

Neglected neuraminidase may explain flu vaccine bloopers

Researchers at the FDA have found that antigenic drift in the neuraminidase of vaccine strains has contributed to the poor protective efficacy of recent influenza vaccines. Protective efficacy of those vaccines has been around 30% at best, and has at times been in the single digits. Explanations for why the efficacy is so low have focused on changes in the hemagglutinin protein. However, the vaccines raise antibodies against both hemagglutinin and neuraminidase, which are the two proteins used to classify viral strains. The FDA team investigated changes in the neuraminidases of the H3N2 strains that have been predominant in recent flu seasons, and they showed that mutations at three specific amino acids impacted binding of antibodies to the protein. "Our findings suggest that NA antigenic drift impacts protection against influenza virus infection, thus highlighting the importance of including NA antigenicity for consideration in the optimization of influenza vaccines," the authors wrote. Their work appeared in the Aug. 12, 2019, issue of Nature Microbiology.

More evidence links Schwann cells to pain

Researchers at the Karolinska Institute have identified a population of Schwann cells in the skin that were able to sense pain. Sensation, including pain sensation, is mostly done by neurons, but the team showed that Schwann cells, which are a type of glial cell, are associated with pain-sensing C fibers in the skin and directly transduced painful mechanical and heat stimuli. Previous work has shown that Schwann cells and C fibers are associated in individuals with neurofibromatosis, where the structures containing both cells were responsible for sensation of pain and itch. The new work, however, demonstrates that Schwann cells themselves sense pain, and that they do so in healthy animals. The authors wrote that "functional implications of our findings are vast if nerve and glial cell receptor types mediate different aspects of thermal and mechanical nociceptive transduction." They reported their findings in the Aug. 15, 2019, issue of Science.

Could orphan opioid receptor prevent opioid orphans?

Opioids continue to provide unrivaled pain relief, but their addictive potential has also led to an unrivaled public health crisis. Now, researchers at the Scripps Research Institute have identified an orphan G protein-coupled receptor (GPCR) that influenced the sensitivity to opioids in C. elegans that expressed a transgenic mu opioid receptor (MOR). Screening for interactions of the opioid receptor with other genes showed that GPR-319 influenced both the analgesic and rewarding effects of opioid administration. In mice, the team showed that treatment with a GPR-319 agonist, reduced both the analgesic effects of morphine and the self-administration of drug by addicted animals. "GPR-139 could be a useful target for increasing opioid safety," the authors concluded. Additionally, "these results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of GPCR signaling principles." They reported their results in the Aug. 15, 2019, issue of Science.

Identifying the cause of lupus cognitive dysfunction

Systemic lupus erythematosus (lupus) is an autoimmune disease that leads to cognitive symptoms in some patients. Researchers from SUNY Downstate Medical Center have identified auto-antibodies in patients with lupus, but not with other autoimmune diseases, that were directed against neuronal regulatory RNAs called brain cytoplasmic (BC) RNAs. The autoantibodies impaired transport of neuronal proteins to the dendrites. In animal experiments, lack of BC RNAs caused cognitive dysfunction, as well as epileptic fits. The authors concluded that "the combined data indicate a role for anti-BC RNA autoimmunity in [lupus] and its neuropsychiatric manifestations." Their study was published in the Aug. 13, 2019, issue of the Journal of Neuroscience.

Microbiome boosts host defense against chlamydia

Lack of lactobacilli in the vaginal microbiome raises women's risk of contracting multiple sexually transmitted infections, including Chlamydia trachomatis, which is the most common STI in the U.S., and Neisseria gonorrhea, which is becoming untreatable as antibiotic-resistant strains spread. Researchers from the University of Maryland School of Medicine have demonstrated that this protection was partly due to the production of one isoform of lactic acid, D-lactic acid. Lactobacillus strains that did not produce D-lactic acid were less protective than those that did. The D-lactic acid produced by the microbiome did not primarily kill the pathogen; instead, it was protective because it altered the epigenetic profile of vaginal epithelial cells. The work appeared in the Aug. 13, 2019, issue of mBio.

What wakes up CMV

Researchers at the University of Arizona at Tucson have gained new insights into the reactivation of cytomegalovirus (CMV) from latency. CMV is a herpesvirus that establishes chronic but usually latent infections. In immunocompromised individuals, however, the virus can escape immune control and cause life-threatening infections. Researchers have assumed that escape occurs when the host immune system becomes unable to suppress the major immediate early promoter (MIEP) that drives the expression of key viral proteins. The authors, however, found that the MIEP remained silent during reactivation. Instead, alternative promoters located in the same general region of the viral genome were responsible for driving gene expression during reactivation. The authors wrote that "this finding represents a major paradigm shift, demonstrating the use of alternative promoters to drive virus reactivation in a context-dependent manner." Their work appeared in the Aug. 13, 2019, online issue of the Proceedings of the National Academy of Sciences.

Malaria vaccine has indirect protective effects

Investigators at the University of Barcelona's ISGlobal Hospital Clinic have demonstrated that vaccination with the RTS,S malaria vaccine strengthened the antibody immune response to antigens that are not part of the vaccine, contributing to clinical protection. The malaria parasite has a complicated life cycle, and because the RTS,S vaccine is not sterile, one possibility is that reduced antibody production could lead to increased vulnerability once effects of the vaccine itself waned. However, the authors found that "antibodies to certain antigens which may be targets of protective [naturally acquired immunity] may be enhanced by RTS,S/AS01E vaccination, contributing to vaccine efficacy. These antigens could potentially be candidates of multivalent next-generation RTS,S formulations to improve vaccine efficacy as additive (or synergistic) responses with CSP" – the major RTS,S antigen – "may occur." They reported their findings in the Aug. 14, 2019, online issue of BMC Medicine.

TREM2 may play role in AD patients without risk variant

Researchers at Washington University in St. Louis have discovered that the membrane-spanning 4-domains subfamily A (MS4A4A) gene modulated both the triggering receptor expressed on myeloid cells 2 (TREM2) and the risk of Alzheimer's disease (AD). Certain TREM2 variants increase the risk of AD more than any other variant besides APOE. In their work, the authors analyzed genome-wide association study (GWAS) data from AD patients to find genes that interacted with TREM2, and they found that MS4A4A modulated TREM2 expression. The authors said their findings "suggest that MS4A4A modulates sTREM2," the authors wrote. "These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease." Their work appeared in the Aug. 14, 2019, issue of Science Translational Medicine.

No Comments