Month: December 2022

UCI-led study shows cognitively impaired degu is a natural animal model well suited for Alzheimer’s research

Chilean degu rodents display behavioral and neuropathological features that resemble human Alzheimer’s Disease

Immunofluorescence confocal microscopy shows that reactive astrocytes (green) surround amyloid plaques (red) in the aged, outbred degu brain.

Irvine, CA – December 19, 2022 – Led by researchers from the University of California at Irvine, a new study reveals that a long-lived Chilean rodent, called Octodon degus (degu), is a useful and practical model of natural sporadic Alzheimer’s Disease. The findings were published today in Acta Neuropathologica Communications.

“We found robust neurodegenerative features in cognitively impaired aged degus, including hippocampal neuronal loss, altered parvalbumin and perineuronal net staining in the cortex, and increased c-Fos neuronal activation in the cortex that is consistent with the neural circuit hyperactivity that are commonly reported in human Alzheimer’s Disease patients,” explained corresponding author Xiangmin Xu, PhD, professor and Chancellor’s Fellow of anatomy and neurobiology in the UCI School of Medicine, and director of the Center for Neural Circuit Mapping. “By focusing on a subset of aged degus that show AD-like behavioral deficits and correlative neuropathology, we establish outbred degus as a natural model of sporadic AD and demonstrate the potential importance of wild-type outbred genetic backgrounds for AD pathogenesis.”

This study was motivated by the need to settle earlier debates of whether degus can be a useful natural model of AD.  There is a critical need for non-murine, natural animal models for Alzheimer’s research as particularly highlighted by the NIH RFA “New/Unconventional Animal Models of Alzheimer’s Disease.”  The handful of published papers on degus of differing genetic backgrounds yield inconsistent findings about sporadic AD-like pathological features, with notably differing results between lab in-bred degus versus outbred degus.

“We suspect that inconsistent findings between different studies may have been due to comparing neuropathology results from laboratory in-bred colonies versus more genetically diverse outbred degus, relatively low statistical power for sample size, and the absence of behavioral screening,” said Xu.

This study revealed that outbred, aged degus possessing both behavioral and neuropathological characteristics that resemble human AD pathologies, have clear advantages over common rodent models (mice and rats) for studying AD. Further, a portion of the outbred degu population naturally develops additional conditions similar to type-2 diabetes, macular degeneration, and atherosclerosis with age, which provides an avenue to investigate AD comorbidities in the degu.

“Our findings, taken together, show spontaneous AD-like correlative phenotypes in cognitive performance and neuropathology in aged, outbred degus. This supports that aged degus are a useful and practical model of natural sporadic AD,” said Xu.

Zhiqun Tan, PhD, an associate researcher with UCI’s CNCM and UCIMIND, and B. Maximiliano Garduño, a graduate student in the UCI Department of Anatomy & Neurobiology, are co-first authors of the paper.  Other members of the research team include Todd Holmes, PhD, from the UCI School of Medicine Department of Physiology & Biophysics; Lujia Chen, a graduate student in biomedical engineering at UCI; and their international collaborators Patricia Cogram, PhD, associate professor, and Pedro Fernández Aburto, PhD, from the Institute of Ecology and Biodiversity at the University of Chile.  This study was supported by the National Institutes of Health.

Alzheimer disease (AD) is an age-related progressive neurodegenerative disorder characterized by irreversible cognitive decline and specific pathologic lesions in the brain that greatly impair the lives of individuals suffering from the condition. There are approximately 44 million people suffering from AD worldwide, of which over 90 percent of those cases are late-onset and occur sporadically.

https://www.som.uci.edu/news_releases/degu_natural_animal_model.asp

CNCM Members Recognized in Irvine Standard’s “10 leaders at the center of Irvine’s health care”

MAPPING THE HUMAN BRAIN

Xiangmin Xu leads a UCI interdisciplinary team – including neuroscientists, engineers, virologists, computer scientists and mathematicians – that is raising new hope for early treatments of crippling brain disorders such as Alzheimer’s, depression and epilepsy. In September, Xu’s Center for Neural Circuit Mapping began collaborating with two other institutions on a five-year project, backed by $126 million in federal funds, to map the human brain in unprecedented molecular detail.

“What is most exciting about our work is that we have the potential to identify early warning signs of disorders such as Alzheimer’s disease when they are still treatable,” he says.

In a key breakthrough, Xu, a professor in the Department of Anatomy and Neurobiology, says he and his collaborators have already discovered ways to reopen windows of neural development in adults, paving the way for previously unthinkable remedies.

LAYING THE GROUNDWORK FOR RNA VACCINES

With life approaching a pre-pandemic norm, Philip Felgner is feeling justifiably proud.

Felgner, 72, UCI’s director of Vaccine Research and Development Center, has spent more than half of his lifetime helping to lay the groundwork for the cutting-edge messenger RNA vaccines that have saved countless lives.

Older vaccines stimulated the body’s immune system with weak or inactive viruses or bacteria. The game-changing new vaccines deployed in the pandemic instead use genetically engineered mRNA to teach cells to make a protein that triggers an immune response.

Felgner’s contributions date to his 1984 discovery of lipofection technology, in which scientists insert genetic material into a liposome – an artificial nanoparticle – to deliver it to cells. Since then, hundreds of other researchers have helped develop the field.

Last year, Felgner was one of seven scientists to win Spain’s prestigious Princess of Asturias Award, but he isn’t resting on his laurels. At the start of the pandemic, in February 2020, his lab began monitoring local virus exposure and later measured the stunning efficacy of the mRNA vaccines.

“My proudest moment is now,” he says, “to see the results of my contribution and those of hundreds of other scientists come to fruition in such a dramatic way.”