No new neurons

One theory for how antidepressants exert their effects, and why they take weeks to do so, is that they stimulate the growth of new neurons in the brain, in particular in the hippocampus. A group from the University of California at San Francisco have cast doubt on that mechanism. The researchers looked at about 60 human brain samples, both postmortem and from epilepsy surgeries. While they were able to see clear evidence of developing neurons in fetal brain samples with their technique, they were not able to detect young neurons in 30 adult brain samples. "We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans," they wrote. "The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved." Their work appeared in the March 8, 2018, issue of Nature.

What triggers TREM2? Amyloid beta

Triggering receptor expressed on myeloid cells 2 (TREM-2) mutations affect the risk of developing Alzheimer's disease (AD), but both its binding partners that contribute to AD and the molecular mechanisms that increase risk have been unknown. Now, researchers from the Sanford Burnham Prebys Medical Research Institute (SBP) and the University of California at Los Angeles have reported that TREM-2's partner in crime is none other than amyloid beta itself. Trem-2 binding to amyloid beta activated microglia, and those microglia in turn were able to clear A-beta, which reduced AD symptoms in a mouse model of AD. The authors said that "as current strategies targeting A-beta generation and use of Ab antibody clearance have seen little success, modulation of microglial clearance through receptors such as TREM-2 may be a favorable alternative for future pharmacological development." The papers appeared back to back in the March 8, 2018, issue of Neuron.

Pain neurons play role in lung infections

Targeting neuroimmunological signaling may be a novel approach to treating infections. Previous work has shown that pain receptors that innervate the lungs are protective in infections because they mediate coughing and constriction of the bronchi, as well as pain. Additionally, pain neurons interact directly with the immune system. Researchers from Harvard Medical School investigated whether that neuroimmune crosstalk had an effect on the immune response to infections. They showed that in mice the activation of pain neurons exacerbated Staphylococcus aureus infection in the lungs, and animals lacking the pain receptor were able to survive an otherwise lethal bout of pneumonia. "The increased prevalence of multidrug-resistant bacteria including methicillin-resistant S. aureus (MRSA) strains necessitates non-antibiotic approaches to treatment," the authors wrote. "Targeting neuroimmunological signaling may be a novel approach to boost host immunity against lung pathogens." The team published its results in the March 5, 2018, online issue of Nature Medicine.

Giving E. coli an attachment disorder

Urinary tract infections mediated by Escherichia coli may also be susceptible to non-antibiotic approaches to treatment, a team from Washington University in St. Louis reported. Uropathogenic Escherichia coli (UPEC) uses structures tipped with adhesin proteins to bind to carbohydrate molecules in different tissues. The team used structure-guided design to create decoy carbohydrates that bound to E. coli's adhesion proteins, preventing the bacteria from colonizing the urinary tract and kidneys. The authors concluded that their decoys "represent a rational antivirulence strategy for UPEC-mediated UTI treatment." Their work appeared in the March 5, 2018, issue of the Proceedings of the National Academy of Sciences.

Metastasis begins at home

Metastatic breast cancer remains incurable, and mutations within a single patient can differ significantly from each other, as well as the primary tumor. To gain a better understanding of the natural history of metastatic breast cancer, researchers from the University of North Carolina at Chapel Hill compared DNA and RNA sequencing data from primary tumors and almost 70 metastases across multiple anatomical sites in a group of 16 patients. They showed that "genetic drivers were predominantly established in the primary tumor and maintained through metastatic spreading. In addition, our analyses revealed that most genetic drivers were DNA copy number changes, the TP53 mutation was a recurrent founding mutation regardless of subtype, and that multiclonal seeding of metastases was frequent and occurred in multiple subtypes. Genetic drivers unique to metastasis were identified as somatic mutations in the estrogen and androgen receptor genes. These results highlight the complexity of metastatic spreading, be it monoclonal or multiclonal, and suggest that most metastatic drivers are established in the primary tumor, despite the substantial heterogeneity seen in the metastases." The work appeared in the Feb. 26, 2018, issue of the Journal of Clinical Investigation.