“We have identified a new trigger of brain inflammation in these disorders,” said Elizabeth Ochoa, PhD, study author from UT Health San Antonio. The finding published in Science Advances is novel for this reason, she said.

Ochoa, a recent doctoral graduate, and her mentor, Bess Frost, PhD, study senior author, are investigators with the Sam and Ann Barshop Institute for Longevity and Aging Studies, the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, and the Department of Cell Systems and Anatomy at UT Health San Antonio. Frost is the Bartell Zachry Distinguished Professor for Research in Neurodegenerative Disorders.

Alzheimer’s disease and progressive supranuclear palsy are marked by toxic deposits of a protein called tau. Their research found that tau-induced “jumping genes” — which can relocate or copy themselves to other locations in the genome — form double-stranded RNA. This abnormal RNA mimics the inflammatory trigger that is also present in viral infections.

“Transposable elements — the so-called jumping genes — are a new area of interest in understanding Alzheimer’s disease. Our study provides new insights into how they can drive the disease process in addition to their ability to jump,” Ochoa said. “These double-stranded RNAs look like a virus to the immune system even though the jumping genes are a part of our normal genome.”

The researchers detected accumulation of double-stranded RNA in postmortem brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy and in brains of mouse and fruit fly models of tauopathy.

“We found substantial deposits of double-stranded RNA in astrocytes, which are cells that provide metabolic support for neurons, regulate neurotransmitters and maintain blood-brain barrier integrity,” Frost said. “In aging and disease, astrocytes respond to injury and disruption of the neuronal environment. Our findings open new doors for understanding astrocyte biology and their role in transposable element control.”

Loss of neurons, which are cells of the central nervous system, is progressive in Alzheimer’s and other neurodegenerative diseases.

The researchers conducted experiments in fruit flies to quickly test their questions about double-stranded RNA and inflammation in the brain. “To ensure that what we found in our fruit fly experiments is relevant to mammalian disease, we also studied brain tissue from mouse models and from postmortem human brains affected by tauopathy,” Ochoa said.

“As we are currently targeting jumping gene activation in a local Phase II clinical trial for patients with Alzheimer’s disease, it’s important to understand the full repertoire of toxic molecules, including double-stranded RNAs, that jumping genes produce,” Frost said.

Ochoa recently earned her PhD from the Cell Biology, Genetics and Molecular Medicine Discipline of the Integrated Biomedical Sciences program at UT Health San Antonio. She earned her undergraduate degree from Seattle University.

Frost, associate professor of cell systems and anatomy in the Barshop and Biggs institutes at UT Health San Antonio, received the highly competitive Edith and Peter O’Donnell Award in Medicine in 2020 from TAMEST, the Texas Academy of Medicine, Engineering, Science and Technology. She was also a Gold Medalist in 2022 for the Oskar Fischer Prize.

Acknowledgments

This study was supported by the National Institute of Neurological Diseases and Stroke, the Rainwater Foundation and the National Institute of General Medical Sciences. Coauthor Kevin Bieniek, PhD, is the director of the UT Health San Antonio Glenn Biggs Institute Brain Bank, which is supported by the National Institute on Aging, the Texas Alzheimer’s Research and Care Consortium, the Bill and Rebecca Reed Precision Medicine Center and the Bartell and Mollie Zachry Endowment for Alzheimer’s Research and Patient Care.

The Mayo Clinic Brain Bank provided human brain tissue. Coauthor William Ray, PhD, of the Neurodegeneration Consortium, Therapeutics Discovery Division at The University of Texas MD Anderson Cancer Center provided mouse brain tissue for analyses.

These cells assemble and maintain their own smaller, internal bits: the membrane-bound organelles like nuclei, which store genetic information, or mitochondria, which produce chemical energy. But much remains to be learned about how they organize themselves into these spatial compartments.

Physicists at Washington University in St. Louis conducted new experiments that show that eukaryotic cells can robustly control average fluctuations in organelle size. By demonstrating that organelle sizes obey a universal scaling relationship that the scientists predict theoretically, their new framework suggests that organelles grow in random bursts from a limiting pool of building blocks.

The study was published Jan. 6 in Physical Review Letters.

“In our work, we suggest that the steps by which organelles are grown — far from being an orderly ‘brick-by-brick’ assembly — occur in stochastic bursts,” said Shankar Mukherji, assistant professor of physics in Arts & Sciences.

“Such bursts fundamentally limit the precision with which organelle size is controlled but also maintain noise in organelle size within a narrow window,” Mukherji said. “Burstlike growth provides a general biophysical mechanism by which cells can maintain, on average, reliable yet plastic organelle sizes.”

Organelles must be flexible enough to allow cells to grow or shrink them as environments demand. Still, the size of organelles must be maintained within certain limits. Biologists have previously identified certain molecular factors that regulate organelle sizes, but this study provides new insights into the quantitative principles underlying organelle size control.

While this study used budding yeast as a model organism, the team is excited to explore how these assembly mechanisms are utilized across different species and cell types. Mukherji said that they plan to examine what these patterns of robustness can teach us about how to harness organelle assembly for bioengineering applications and how to spot defects in organelle biogenesis in the context of disease.

“The pattern of organelle size robustness is shared between budding yeast and human iPS cells,” Mukherji said. “The underlying molecular mechanisms producing these bursts are yet to be fully elucidated and are likely to be organelle-specific and potentially species-specific.”

Funding: This research was supported by the National Institutes of Health (NIH R35GM142704).

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Materials provided by Washington University in St. Louis. Original written by Talia Ogliore. Note: Content may be edited for style and length.

A team of researchers, led by Young-Shin Jun, professor of energy, environmental & chemical engineering in the McKelvey School of Engineering at Washington University in St. Louis, analyzed how light breaks down polystyrene, a nonbiodegradable plastic from which packing peanuts, DVD cases and disposable utensils are made. In addition, they found that nanoplastic particles can play active roles in environmental systems. In particular, when exposed to light, the nanoplastics derived from polystyrene unexpectedly facilitated the oxidation of aqueous manganese ions and formation of manganese oxide solids that can affect the fate and transport of organic contaminants in natural and engineering water systems.

The research, published in ACS Nano Dec. 27, 2022, showed how the photochemical reaction of nanoplastics through light absorption generates peroxyl and superoxide radicals on nanoplastic surfaces, and initiates oxidation of manganese into manganese oxide solids.

“As more plastic debris accumulates in the natural environment, there are increasing concerns about its adverse effects,” said Jun, who leads the Environmental Nanochemistry Laboratory. “However, in most cases, we have been concerned about the roles of the physical presence of nanoplastics rather than their active roles as reactants. We found that such small plastic particles that can more easily interact with neighboring substances, such as heavy metals and organic contaminants, and can be more reactive than we previously thought.”

Jun and her former student, Zhenwei Gao, who earned a doctorate in environmental engineering at WashU in 2022 and is now a postdoctoral scholar at the University of Chicago, experimentally demonstrated that the different surface functional groups on polystyrene nanoplastics affected manganese oxidation rates by influencing the generation of the highly reactive radicals, peroxyl and superoxide radicals. The production of these reactive oxygen species from nanoplastics can endanger marine life and human health and potentially affects the mobility of the nanoplastics in the environment via redox reactions, which in turn might negatively impact their environmental remediation.

The team also looked at the size effects of polystyrene nanoplastics on manganese oxidation, using 30 nanometer, 100 nanometer and 500 nanometer particles. The two larger-sized nanoparticles took longer to oxidize manganese than the smaller particles. Eventually, the nanoplastics will be surrounded by newly formed manganese oxide fibers, which can make them easily aggregated and can change their reactivities and transport.

“The smaller particle size of the polystyrene nanoplastics may more easily decompose and release organic matter because of their larger surface area,” Jun said. “This dissolved organic matter may quickly produce reactive oxygen species in light and facilitate manganese oxidation.”

“This experimental work also provides useful insights into the heterogeneous nucleation and growth of manganese oxide solids on such organic substrates, which benefits our understanding of manganese oxide occurrences in the environment and engineered materials syntheses,” Jun said. “These manganese solids are excellent scavengers of redox-active species and heavy metals, further affecting geochemical element redox cycling, carbon mineralization and biological metabolisms in nature.”

Jun’s team plans to study the breakdown of diverse common plastic sources that can release nanoplastics and reactive oxidizing species and to investigate their active roles in the oxidation of transition and heavy metal ions in the future.

Funding for this research was partially provided by the National Science Foundation (CHE-1905077) and the McDonnell International Scholars Academy at Washington University in St. Louis.

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Materials provided by Washington University in St. Louis. Original written by Beth Miller. Note: Content may be edited for style and length.

While buildup of amyloid protein has been associated with Alzheimer’s-related neurodegeneration, little is known about how the protein relates to normal brain aging, said University Professor Caleb Finch, the study’s senior author and holder of the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging at the USC Leonard Davis School.

To explore the levels of Aβ in human brains, the researchers analyzed tissue samples from both healthy brains and brains of patients with dementia. More severe Alzheimer’s cases were indicated by higher Braak staging scores, a measurement of how widely signs of Alzheimer’s pathology are found within the brain.

The analysis revealed that older, cognitively healthy brains showed similar amounts of dissolvable, non-fibrillar amyloid protein as brains of Alzheimer’s patients. But, as the researchers expected, the brains of Alzheimer’s patients had higher amounts of insoluble Aβ fibrils, the form of amyloid protein that aggregates to form the telltale “plaques” seen in the disease, said Max Thorwald, the study’s first author and a postdoctoral researcher at the USC Leonard Davis School.

The findings challenge the idea that simply having higher amounts of amyloid protein in general is an underlying cause of Alzheimer’s, say Finch and Thorwald. Instead, the increase in soluble Aβ may be a general aging-related change in the brain not specific to Alzheimer’s, while higher levels of fibrillary amyloid appear to be a better indicator of poorer brain health.

Rather than Alzheimer’s simply involving increased production of Aβ protein, the more important issue may be a reduced ability to effectively clear the protein and stave off the creation of plaque-contributing fibrillary amyloid, Thorwald said.

“These findings further support the use of aggregated, or fibrillary, amyloid as a biomarker for Alzheimer’s treatments,” Thorwald said. “The site in which amyloid processing occurs has less precursor and enzyme available for processing, which may suggest the removal of amyloid as a key issue during Alzheimer’s.”

Increases in amyloid levels happen during early adulthood and differ by brain region. Further studies, including those investigating drugs to possibly break down amyloid, should incorporate positron emission tomography (PET) imaging in both healthy individuals and Alzheimer’s patients of a wide range of ages to determine how and where amyloid processing and removal changes in the brain over time, he added.

“The brain’s frontal cortex has more amyloid production compared to the cerebellum during the aging process in human brains, which coincides with their Alzheimer’s-correlated pathologies in late life,” Thorwald said. “Future projects should examine amyloid over the life course in both cognitively normal and Alzheimer’s patients with both modulation of amyloid processing or removal of amyloid through monoclonal antibodies currently used in clinical trials for Alzheimer’s treatment.”

Monoclonal antibody treatment lemanecab has been observed to reduce Aβ plaques in clinical trials and recently received FDA approval for its potential to slow cognitive decline in Alzheimer’s patients, but the results warrant further careful research regarding long-term impact, Finch said.

“Lecanemab clearly works to diminish fibrillar amyloid,” he said. “However, we are concerned with major side effects, including brain swelling and bleeding, that were 100% more than in controls, with unknown delayed or latent impact.”

Learning more about how the brain processes and removes proteins such as Aβ could provide important insights into Alzheimer’s disease and its causes. Finch noted that very few cases of dementia occur with amyloid plaques, or masses of aggregated Aβ protein, as the only pathology present in affected patients’ brains. Instead, most cases present with more complicated tissue abnormalities, from buildup of additional types of protein to small bleeds in the brain: “The aging brain is a jungle.”

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Materials provided by University of Southern California. Original written by Beth Newcomb. Note: Content may be edited for style and length.