Brain diseases associated with the misformed protein tau, including Alzheimer's disease and frontotemporal lobar degeneration with tau pathologies, are characterized by neurofibrillary tangles (NFTs) comprised of pathological tau filaments. Tau tangles are also found in progressive supranuclear palsy, cortical basal degeneration and other related tauopathies, including chronic traumatic encephalopathy due to repetitive traumatic brain injuries sustained in sports or on the battle field.
By using synthetic fibrils made from pure recombinant protein, Penn researchers provide the first direct and compelling evidence that tau fibrils alone are entirely sufficient to recruit and convert soluble tau within cells into pathological clumps in neurons, followed by transmission of tau pathology to other inter-connected brain regions from a single injection site in an animal model of tau brain disease.
The laboratory of senior author Virginia M.-Y. Lee, Ph.D., MBA, director of the Center for Neurodegenerative Disease Research and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, published their findings in the Journal of Neuroscience this week.
"Our new model of tau pathology spread provides an explanation to account for the stereotypical progression of Alzheimer's and other related tauopathies by implicating the cell-to-cell transmission of pathological tau in this process," says Lee.
Young mice overexpressing mutant human tau were injected with synthetic preformed tau fibrils. These fibrils were assembled from recombinant full-length tau or truncated tau containing four microtubule-binding repeats. The synthetic tau fibrils caused rapid induction of NFT-like inclusions in the brains of the mice. These inclusions then propagated from injected sites to connected brain regions in a dose- and time-dependent manner.
Interestingly, injection of the synthetic tau fibrils into either the hippocampus or the striatum and cortex led to distinctly different patterns of spreading, which is reflective of their functional connectivities. The simplest explanation for this phenomenon is that the injected pathological tau is taken up by the processes of normal neurons where it then corrupts the tau in these nerve cells followed by the transport of the corrupted tau along processes where it is released, taken up by other neurons. Then the cycle repeats itself over and over again, thereby driving disease progression, say the researchers.
What's more, unlike tau pathology that spontaneously develops in older Alzheimer's mice, the inclusions induced by the synthetic tau injections in the younger mice more closely resembled Alzheimer's tangles in their physical and biochemical make-up.
The study demonstrates that synthetic tau fibrils alone are capable of inducing authentic NFT-like tau clumps and initiating spreading of tau pathology in an Alzheimer's mouse model.
The team is now conducting studies to identify monoclonal antibodies for passive immunotherapies related to tau pathologies.
"We are also exploring the mechanisms of spreading and the relationship of tau tangles with senile plaques," says Lee. "We believe that this newly described transmission model may more faithfully recapitulate human Alzheimer's pathogenesis than the conventional transgenic mouse models of overexpressing mutant genes that develop aggregates. Exploring if this injection-transmission model is more appropriate for the progression of Alzheimer's, as well as Parkinson's, is another priority."
University of Pennsylvania School of Medicine: http://www.uphs.upenn.edu/news/
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
A riverside in Nebraska is a welcome refuelling stop for these elegant birds migrating from Mexico to their breeding grounds
Deprived of sight, blind people manage to squeeze an amazing amount of information out of their other senses. Doing this requires their brains to do some reorganizing. To learn about some of these changes, scientists studied the brains of blind people ...
In 1973, American soldiers on the Mekong River in Laos killed and hauled ashore a massive 24-foot ribbon of a fish. It was the “Queen of the Naga,” claimed a postcard still widely circulated in Southeast Asia with the above ...
Bald eagles have made a comeback. See life in the nest now during peak nesting season.
Photos capture a river otter attacking a gator in a Florida river. The otter then feasted, witnesses say.
The 10-meter long Torvosaurus weighed up to five tons.
Researchers say the key to fighting superbugs is individualized treatment plans, and a new nanochip might pave the way
Some farmers have long sworn by mellow tunes to boost Bessie's milk production. The science is hardly conclusive. But a study hints at what might top the barnyard playlist. (Psst: They liked R.E.M.)
Craig Venter, the U.S. scientist who raced the U.S. government to map the human genome over a decade ago and created synthetic life in 2010, is now on a quest to treat age-related disease.
Dr Dave Hone: The Daohugou Fauna is rich in dinosaurs, lizards, pterosaurs, salamanders and mammalsDr Dave Hone