More human-like model of Alzheimer's better mirrors tangles in the brain

November 16, 2016

PHILADELPHIA--Tangled up brain fibrils made up of a rogue protein known as tau are the hallmark of Alzheimer's disease (AD) that likely hold the key to treatments, making them of great interest to researchers. Mimicking the formation and spread of these tangles in animal models with greater accuracy allows scientists to better investigate new therapies to stop or slow their spread.

A new animal model developed at Penn Medicine using tau tangles isolated from the brains of Alzheimer's patients rather than synthetic tau tangles paints a closer picture of the tau pathology in the AD brain, researchers from the Center for Neurodegenerative Disease Research (CNDR) at the Perelman School of Medicine at the University of Pennsylvania reported in the print issue of the Journal of Experimental Medicine. Seeding normal, wildtype mice with the highly potent Alzheimer's brain-tau (AD-tau) protein induced damaging tangles in their brains for study, mirroring a more realistic progression of tau tangles seen in AD patients' brains.

Importantly, the mice used in the experiment were non-transgenic, meaning they did not overexpress tau protein. Past animal studies, including research from Penn Medicine, using synthetic tau fibrils provided an explanation for the progression of Alzheimer's and other related tauopathies by implicating the cell-to-cell transmission of pathological tau. However, this phenomenon was only demonstrated in models overexpressing tau. But increased tau expression is not a cause of Alzheimer's or other conditions involving misshapened tau protein.

"Alzheimer's patients don't generally overexpress tau or harbor tau mutations, so it was important to develop a model that can recreate the pathology in a setting that more closely resembles what's happening in patients," said senior author Virginia M.-Y. Lee, PhD, MBA, CNDR director and a professor of Pathology and Laboratory Medicine. "This model will open up many new directions and opportunities for not just Alzheimer's, but also for other pathological tau disorders, such as corticobasal degeneration [CBD] and progressive supranuclear palsy [PSP], conditions which cause Parkinson-like symptoms, but CBD and PSP also are associated with cognitive impairments that mimic Alzheimer's."

Normal tau keeps nerve cells functioning properly, but pathological tau can cause the protein to go rogue, or misfold, triggering the formation of protein clumps known as neurofibrillary tangles, which are tightly linked to AD. It has been shown to move from cell to cell to form tangles in the brain, first in the areas that make memories, and then outward to areas associated with remembering.

Synthetic tau tangles have been used in transgenic mice to pattern this spread by Penn and others in the field, but until now, it couldn't produce enough misshapened tau protein in normal mice to fully support this hypothesis.

This is the first time, to the authors' knowledge, researchers have shown abundant amounts of tau tangles convincingly induced in multiple brain regions within a few months after inoculation of AD-tau. This observation provides the strongest support thus far for the physiological relevance of cell-to-cell transmission of pathological tau in human tauopathies, the authors said.

"This relevant mouse model will allow us to better study the architecture of tau and its physiological consequence in mechanistic and therapeutic investigations," Lee said, "but it also provides an experimental paradigm to examine how other factors, such as amyloid plaques, another hallmark of AD, contribute to the spreading, and how tau spreads in other diseases, like CBD and PSP, among other important questions that need to be answered."
-end-
Penn co-authors include Jing L. Guo, Sneha Narasimhan, Lakshmi Changolkar, Zhuohao He, Anna Stieber, Bin Zhang, Ronald J. Gathagan, Michiyo Iba, Jennifer D. McBride, and John Q. Trojanowski.

This work was funded by the National Institutes of Health (AG10124 and AG17586), CurePSP, the Woods Foundation, and the BrightFocus Foundation (A2014005F).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania(founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.

University of Pennsylvania School of Medicine

Related Brain Articles from Brightsurf:

Glioblastoma nanomedicine crosses into brain in mice, eradicates recurring brain cancer
A new synthetic protein nanoparticle capable of slipping past the nearly impermeable blood-brain barrier in mice could deliver cancer-killing drugs directly to malignant brain tumors, new research from the University of Michigan shows.

Children with asymptomatic brain bleeds as newborns show normal brain development at age 2
A study by UNC researchers finds that neurodevelopmental scores and gray matter volumes at age two years did not differ between children who had MRI-confirmed asymptomatic subdural hemorrhages when they were neonates, compared to children with no history of subdural hemorrhage.

New model of human brain 'conversations' could inform research on brain disease, cognition
A team of Indiana University neuroscientists has built a new model of human brain networks that sheds light on how the brain functions.

Human brain size gene triggers bigger brain in monkeys
Dresden and Japanese researchers show that a human-specific gene causes a larger neocortex in the common marmoset, a non-human primate.

Unique insight into development of the human brain: Model of the early embryonic brain
Stem cell researchers from the University of Copenhagen have designed a model of an early embryonic brain.

An optical brain-to-brain interface supports information exchange for locomotion control
Chinese researchers established an optical BtBI that supports rapid information transmission for precise locomotion control, thus providing a proof-of-principle demonstration of fast BtBI for real-time behavioral control.

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.

Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.

Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.

Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.

Read More: Brain News and Brain Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.