A Molecular Switch for Alzheimer’s Inflammation

S-nitrosylation of STING emerges as a driver of neuroinflammatory signaling in Alzheimer’s disease 

A new study from scientists at Scripps Research has identified a chemical modification of stimulator of interferon genes (STING) that may help drive the chronic neuroinflammation seen in Alzheimer’s disease. Across human postmortem brain tissue, stem cell-derived human brain immune cells, and a transgenic mouse model, the team, working in collaboration with John Yates, identified S-nitrosylation of STING at cysteine 148 as a change associated with excessive type I interferon signaling, microglial activation, and synaptic damage. 

The team used a combination of redox chemical biology and mass spectrometry to pinpoint the modification site and link it to STING oligomerization. In human Alzheimer’s brain samples and disease-relevant cell models, they detected elevated levels of S-nitrosylated STING, while laboratory experiments suggested that amyloid-beta and alpha-synuclein aggregates can trigger the same reaction. Together, the findings place a specific post-translational modification upstream of a broader inflammatory loop in which protein aggregates, nitrosative stress, and innate immune signaling reinforce one another. 

The researchers then engineered a version of STING lacking cysteine 148, preventing the modification from forming. In an Alzheimer’s mouse model, that intervention reduced neuroinflammatory signaling and protected synapses from degeneration. “This is a new and important therapeutic target for Alzheimer’s disease,” says senior author Stuart Lipton in the team’s press release. 

“It’s exciting to see that blocking this switch in mice reduces inflammation and protects the very brain cell connections that are lost in Alzheimer’s, especially because we found the same pathway to be activated in human Alzheimer’s brain samples and in human stem cell-derived models.” 

Lipton’s group is now developing small molecules to block cysteine 148 and test whether selective interference with S-nitrosylated STING can preserve normal immune function while limiting damaging inflammation. 

PFAS in Bottlenose Dolphin Milk May Expose Nursing Calves

Archived milk samples suggest nursing dolphin calves may face substantial early-life PFAS exposure

Nursing dolphin calves may receive substantial early-life exposure to per- and polyfluoroalkyl substances (PFAS) through their mothers’ milk, according to a new longitudinal analysis of archived samples. Working with milk from a single Atlantic bottlenose dolphin, a research team led by Erin Baker detected 30 PFAS in total – with 20 present throughout the nursing window from 103 to 706 days. Perfluorooctanesulfonic acid (PFOS) dominated the mixture and reached its highest concentrations early in lactation, though total PFAS burden rose again later rather than declining uniformly. 

To analyze the high-fat samples, the team miniaturized a QuEChERS-based extraction, a streamlined sample-preparation method, for 1 mL of milk, then coupled reversed-phase liquid chromatography with ion mobility spectrometry and mass spectrometry (LC-IMS-MS). The workflow supported targeted quantitation, suspect screening, and non-targeted analysis on a single platform, capturing both routinely monitored PFAS and compounds often missed by standard targeted assays.  

“Traditional testing methods typically look for a limited number of known PFAS compounds,” said Baker in the team’s press release. “By combining multiple analytical techniques, we can identify a much broader range of chemicals and be more confident in what we are detecting.” 

The broader screen identified 12 additional PFAS, including long-chain sulfonic acids, PFOS precursors, and replacement compounds such as perfluoroethylcyclohexanesulfonate (PFECHS) and 8-chloroperfluorooctanesulfonic acid (8Cl-PFOS). Using allometrically scaled human health benchmarks, the authors estimated that PFOS exposure through milk at around three months of age could exceed tolerable weekly intake guidance by more than 25-fold. 

Future work, the authors suggest, should test whether similar patterns of lactational PFAS transfer hold across other individuals and mammalian species. “Marine mammals can provide insight into how widespread these contaminants are in the environment,” said co-author Weisueh Chiu. 

When the Antarctic Dust Settles 

Single-particle MS reveals major changes in Antarctic dust composition from 44,000 to 9,000 years ago  

Single-particle analysis of Antarctic ice has traced changing dust inputs across the last glacial-to-Holocene transition. In Taylor Glacier samples spanning 44,000 to 9,000 years before present, researchers found major shifts in both particle abundance and composition, with glacial ice containing far more dust and Holocene samples showing relative enrichment in iron-rich material.  

Using single-particle inductively coupled plasma time-of-flight mass spectrometry (spICP-TOFMS), the team characterized more than 2 million particles smaller than 2.5 μm across 28 Taylor Glacier samples, using less than 7 mL of meltwater. By recording elemental mass spectra particle by particle, the method linked concentration, size, and elemental composition directly, rather than inferring them from separate bulk measurements. 

The analysis showed higher proportions of sodium-, magnesium-, and aluminum-bearing particles during the glacial period, while younger samples contained more iron-rich particles, including hematite/goethite-like material. One interval, around 14.8 kyr before present, stood out for larger particles and unusual chemistry; scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS) supported the presence of volcanic glass shards consistent with nearby Victoria Land volcanism. 

“Normally, we are limited with analysis due to our sample volume,” said lead author Stanislav Kutuzov. “But the way this new technique works, it only requires a tiny amount of water to detect a huge amount of information about each particle.” 

The authors say future work should focus on building reference datasets for volcanic glass, minerals, and known dust-source regions. “Using this new method to confirm what was known before with more certainty shows that it could be applied to different places and events where we don’t know what happened,” Kutuzov added. 

Abasic Sites May Be Overlooked in Oxidative DNA Damage Studies 

A mass spectrometry-led study exposes a detection blind spot in oxidative DNA damage analysis 

Oxidative DNA damage has been studied for decades, but a mass spectrometry-led analysis now suggests a major lesion type has been hiding in plain sight. Working with model oligonucleotides, researchers at Tohoku University showed that singlet oxygen can directly generate abasic (AP) sites – positions where a nucleobase is lost – through photocatalytic oxidation, expanding the long-held focus on canonical guanine oxidation products. 

Conventional workflows typically rely on enzymatic digestion followed by ultraviolet (UV)-based detection, which can miss AP sites because they lack the aromatic base required for absorption. By analyzing intact DNA using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and ultra-performance liquid chromatography–electrospray ionization (UPLC-ESI) mass spectrometry, the team detected substantial formation of AP sites alongside established lesions such as spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh). Quantitative analysis showed that AP sites can form at comparable levels to these well-characterized products, suggesting they represent a major, but previously underreported, outcome of oxidative damage. 

Mechanistic experiments point to singlet oxygen as the primary driver, with AP site formation proceeding via an 8-oxo-7,8-dihydroguanine (8-oxoG)-independent pathway. The data indicate that highly solvent-exposed guanine residues – particularly at DNA termini – act as hotspots for this damage, with accessibility rather than sequence alone determining susceptibility. Similar lesions were also observed in RNA and alternative DNA structures, including G-quadruplexes, indicating broader relevance. 

“Our findings reveal that some forms of DNA damage have remained hidden due to limitations in standard detection methods,” said lead author Yuuhei Yamano. “This discovery changes how we understand oxidative DNA damage, opening new possibilities for more accurate studies and improved technologies for working with genetic material.”  

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