Amyloid after amnesia?
A University of California, San Diego-led team from the Alzheimer’s Disease Neuroimaging Initiative has reported that in long-term imaging studies, objective subtle cognitive deficits (obj-SCD) preceded amyloid deposition in longitudinal imaging studies. Repeated imaging over four years of several hundred individuals who had normal cognition, obj-SCD or mild cognitive impairment (MCI) showed that individuals with obj-SCD did not differ from those with normal cognition at baseline in terms of their amyloid plaque levels. They did, however, show thinning of certain memory-associated brain regions. Over the course of the study, individuals with obj-SCD accumulated amyloid plaque and progressed to MCI more rapidly than those who were cognitively normal. The findings cast further doubt on the idea that amyloid plaques are a causal factor in AD. The authors wrote that “Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.” They reported their results in the Dec. 30, 2019, advance online issue of Neurology.
FGF21 switches sides in pancreatitis
Researchers at the University of Texas Southwestern Medical Center have identified low levels of fibroblast growth factor 21 (FGF21) as a driver of pancreatitis. The pancreas produces and secretes digestive enzymes that become activated in the digestive tract. Pancreatitis is the result of too-early activation of those enzymes in the pancreas itself. Previous research had shown that FGF21 levels rise early in pancreatitis. The authors showed that, unexpectedly, that early rise was followed by a decrease in FGF21 levels, and that treatment with FGF21 could ameliorate pancreatitis in several different animal models. They concluded that “whereas previous studies have suggested that [the induced stress response] is an adaptive pathway in acute pancreatitis, we suggest that it becomes maladaptive over time.” Their work appeared in the Jan. 8, 2020, issue of Science Translational Medicine.
Pancreatitis protein promotes pain
Researchers at the Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology have discovered that pancreatitis-associated protein 1 (PAP-1) also played a role in neuropathic pain. The authors showed that in an animal model of neuropathic pain, PAP-1 was up-regulated in the spinal cord after nerve injury. PAP-1 had a proinflammatory effect, activating microglia. Either blocking PAP-1 with an antibody or knocking it out diminished neuropathic pain, leading the authors to conclude that “PAP-1 mediates the neuron-microglial crosstalk after peripheral nerve injury and contributes to the maintenance of neuropathic pain.” They reported their results in the Jan. 7, 2020, online issue of the Journal of Neuroscience.
Treatment effects may spread in LCA gene therapy
Scientists from the University of Pennsylvania have reported preclinical long-term outcomes of RPE65 gene therapy for macular degeneration. Leber congenital amaurosis (LCA) is a hereditary form of blindness that is caused by mutations in both copies of RPE65. Several individuals have been treated with gene therapy as part of a clinical trial, but the long-term outcomes are not yet clear. In their experiments, the team treated middle-aged dogs and followed them for several years. They found that treated regions had to have at least 63% of their photoreceptors left at the time of treatment to fare better than controls. They also found that “both treated and untreated regions in study eyes tended to show less degeneration compared to matched locations in untreated control eyes,” suggesting that “there may be heretofore unknown mechanisms causing long-distance partial treatment effects beyond the region of subretinal injection.” The team reported its results in the Jan. 8, 2020, print issue of Molecular Therapy after earlier publication online.
MRAP2 is accessory after the fact for appetite regulation
Investigators at the University of Iowa have demonstrated new roles for melanocortin receptor accessory protein 2 (MRAP2) in controlling the effects of the so-called “hunger hormone” ghrelin. Ghrelin stimulates appetite and food intake, signaling through the G protein-coupled receptor (GPCR) GHSR-1a. Ghrelin signals both constitutively and in response to agonists, and the authors demonstrated that MRAP2 affected both types of signaling via distinct effects on distinct areas of GSHR-1a. “These findings may have implications for the regulation of ghrelin function in vivo and the role of MRAP2 in energy homeostasis,” the authors wrote. “They also show that accessory proteins can bias signaling downstream of GPCRs in response to their endogenous agonist.” They published their findings in the Jan. 8, 2020, issue of Science Signaling.
Human proteomics study gives new AD insights
A team at St. Jude Children’s Research Hospital has used a combination of human postmortem brain samples and mouse models to analyze proteomic changes over the course of prodromal Alzheimer’s disease (AD). AD has a long prodromal phase where brain changes are already progressing in the absence of clinical symptoms. Mouse models appear to capture the changes that go on in human brains only incompletely, but studying the human brain directly is complicated by the need for postmortem tissues, which are hard to come by and have their own confounders. The authors were able to use human and mouse data in combination to profile almost 15,000 proteins and more than 34,000 phosphorylation sites, and identified roughly 170 proteins in 17 pathways that changed over the course of AD. “The comprehensive multi-omics measurements reveal crucial molecular networks/pathways in AD. AD and mouse model comparison identifies molecular similarities and discrepancies at a global scale, providing evidence to explain the translational gap between mouse models and clinical trials,” the authors wrote. Their work appeared in the Jan. 7, 2020, issue of Neuron.
Macrolide resistance mechanism rescues mRNA from ribosome
Researchers at the New York State Division of Public Health’s Wadsworth Center have identified a new resistance mechanism used by Mycobacterium abscessus, as well as other mycobacterial species. Resistance is typically mediated by bacterial efflux pumps, or enzymes that target the drug itself or alter its bacterial target. The authors showed that deletion of the bacterial hflX gene rendered M. abscessus hypersensitive to macrolide antibiotics, which stall mRNA translation by the ribosome. HflX protein associated with the ribosome and could dissociate its subunits, allowing the mRNA within the ribosomes to dissociate from the stalled ribosome and be translated by another ribosome not bound by drug. “Our results suggest a mechanism of macrolide-lincosamide resistance in which the mycobacterial HflX dissociates antibiotic-stalled ribosomes and rescues the bound mRNA,” the authors wrote. “Given the widespread presence of hflX genes, we anticipate this as a generalized mechanism of macrolide resistance used by several bacteria.” Their work appeared in the Jan. 7, 2020, issue of the Proceedings of the National Academy of Sciences.
New targets, new booster for CAR T cells
Scientists at Biontech Cell & Gene Therapies GmbH have both identified a solid tumor target for CAR T cells and developed a vaccine that improved expansion of those cells. CAR T cells have been transformative for certain B-cell-driven cancers, but their application to solid tumors faces greater challenges and is still in its infancy. One issue is the lack of tumor-specific antigens to rival the B-cell marker CD19. Even CD19-targeted CAR T cells can face exhaustion, a problem that is magnified within the constraints of solid tumors. The team first demonstrated that the protein claudin-6, which is expressed during development, was not found in any normal adult tissues but was frequently expressed by several solid tumor types, including ovarian and lung tumors. The team designed a CAR T cell that was specific to claudin-6 but not to other members of the claudin family. They also adapted an RNA vaccine that stimulates T cells in the bone marrows, lymph nodes and spleen to deliver claudin-6. Together, the two methods were able to achieve “improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models… at sub-therapeutic CAR-T cell doses.” The team reported its results in the Jan. 3, 2020, issue of Science.
As nanoparticles, vitamins fight sepsis
Scientists at Ohio State University have developed cell therapy for sepsis that was able to kill multidrug-resistant bacteria and enabled the recovery of septic mice. While the aspect of sepsis that has received the most attention is its early phase, which is marked by an out of control immune response, the subsequent stage of profound immunosuppression might be equally or more problematic. Furthermore, as the prevalence of multidrug-resistant bacteria continues to increase, treatment has become even more challenging. Using a vitamin C-based nanoparticle, the researchers transfected macrophages with antimicrobial peptides into their lysosomes, and treated septic animals with the altered cells. The authors wrote that further development of the approach “will mainly focus on treating the late phase of sepsis with immunosuppression.” They acknowledged that “the weakness of patients and emergency status of sepsis might make it challenging to collect and engineer autologous macrophages,” a process which takes roughly a week. Nevertheless, they argued, “with the advance of induced pluripotent stem cell technologies, allogeneic ‘universal’ macrophages may be manufactured, enabling MACs derived from induced pluripotent stem cells to become an off-the-shelf therapy for clinical applications, including sepsis.” Their work appeared in the Jan. 6, 2020, online issue of Nature Nanotechnology.
Rett gene affects maternal behavior via cortical plasticity
Scientists at Cold Spring Harbor Laboratory have shown that female mice lacking the MeCP2 gene, which is mutated in Rett syndrome, had reduced plasticity in their auditory cortex in response to pup cries. In previous work, the team had shown that maternal behavior was disrupted in MeCP2 mutant mice, and traced the disruption to cortical interneurons. In follow-up experiments, they showed that in wild-type adult female mice, distress cries of pups led to decreased inhibitory signaling, allowing cortical plasticity. In MeCP2 mutant mice, that plasticity was absent. The results, which suggest that MeCP2-induced deficits might be most amenable to therapeutic intervention during periods of high plasticity, appeared in the Jan. 7, 2020, online issue of the Journal of Neuroscience.