Lifeboat Foundation

Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer’s disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons and identify cholesteryl esters (CE), the storage product of excess cholesterol, as upstream regulators of Tau early during AD development. Using isogenic induced pluripotent stem cell (iPSC) lines carrying mutations in the cholesterol-binding domain of APP or APP null alleles, we found that while CE also regulate Aβ secretion, the effects of CE on Tau and Aβ are mediated independent pathways. Efficacy and toxicity screening in iPSC- derived astrocytes and neurons showed that allosteric activation of CYP46A1 lowers CE specifically in neurons and is well tolerated by astrocytes. These data reveal that CE independently regulate Tau and Aβ and identify a druggable CYP46A1-CE-Tau axis in AD.

Van der Kant et al. performed a repurposing drug screen in iPSC-derived AD neurons and identified compounds that reduce aberrant accumulation of phosphorylated Tau (pTau). Reduction of cholesteryl ester levels or allosteric activation of CYP46A1 by lead compounds enhanced pTau degradation independently of APP and Aβ.

Scientists at the University of Virginia School of Medicine have identified a potential explanation for the mysterious death of specific brain cells seen in Alzheimer’s, Parkinson’s and other neurodegenerative diseases.

The new research suggests that the cells may die because of naturally occurring gene variation in brain cells that were, until recently, assumed to be genetically identical. This variation – called “somatic mosaicism” – could explain why neurons in the temporal lobe are the first to die in Alzheimer’s, for example, and why dopaminergic neurons are the first to die in Parkinson’s.

“This has been a big open question in neuroscience, particularly in various neurodegenerative diseases,” said neuroscientist Michael McConnell of UVA’s Center for Brain Immunology and Glia, or BIG. “What is this selective vulnerability? What underlies it? And so now, with our work, the hypotheses moving forward are that it could be that different regions of the brain actually have a different garden of these [variations] in young individuals and that sets up different regions for decline later in life.”

Continue reading “Brain discovery may explain mysterious cell death in Alzheimer’s, Parkinson’s” »

Gene-edited white blood cells could let us hack our immune systems to prevent infections with pathogens like HIV, flu, and the virus that causes glandular fever.

Squirrel monkeys don’t see color like people. But inject their eyeballs with a genetically engineered virus and they suddenly can perceive a new rainbow. The same trick could someday be used on color-blind people.

Multilateral efforts to decipher the rejuvenation phenomenon of Turritopsis jellyfish at the genetic level also have been initiated by several collaborating research scientists.

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that included the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% CI, confidence interval: 1.13–1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we determined a meta-RR for NHL of 1.45 (95% CI: 1.11–1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed available animal and mechanistic studies, which provided supporting evidence for the carcinogenic potential of GBH. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL. Overall, in accordance with evidence from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.

Researchers from the University of Michigan Rogel Cancer Center have found that a genetic mutation seen in about half of all brain tumors produces a response that prevents radiation treatment from working. Altering that response using FDA-approved drugs restores tumors’ sensitivity to radiation therapy, extending survival in mice.

The paper, representing more than five years of research, is published in Science Translational Medicine.

“These findings have great potential to impact medical treatment of patients with low-grade glioma, which is critically needed for this terrible disease,” says senior author Maria G. Castro, Ph.D., R. C. Schneider Collegiate Professor of Neurosurgery and a professor of cell and developmental biology at Michigan Medicine.

Cancer is a complicated disease. Tumors are made up of many different types of cancer cells, and our current treatment techniques can’t always clear them all out. Now, a team of Oxford researchers has developed a way to track the genetic “life histories” of thousands of individual cancer cells at once, which may lead to more effective and personalized cancer treatments.