Transmission of tangles in Alzheimer's mice provides more authentic model of tau pathology
These are neurons filled with tangles (arrows) in medial region of hippocampus one month after injection of synthetic tau fibrils into the hippocampus. Scale = 50um. Credit: Michiyo Iba, Ph.D., Perelman School of Medicine, University of Pennsylvania
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."
Journal reference: Journal of Neuroscience
Provided by University of Pennsylvania School of Medicine
- Anti-tau drug improves cognition, decreases tau tangles in Alzheimer's disease models Jul 19, 2012 | not rated yet | 0
- Study suggests another avenue for detecting Alzheimer's disease Apr 01, 2011 | not rated yet | 0
- Alzheimer's protein detected in brain fluid of healthy mice Sep 21, 2011 | not rated yet | 0
- Untangling the mysteries of Alzheimer's Feb 02, 2012 | not rated yet | 0
- Acetylation may contribute to dementia and Alzheimer's disease Sep 22, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
How can there be a term called "intestinal metaplasia" of stomach
6 hours ago Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
Ratio of Hydrogen of Oxygen in Dessicated Animal Protein
May 13, 2013 As an experiment, for the past few months I've been consuming at least one portion of Jell-O or unflavored Knox gelatin per day. I'm 64, in very...
Alcohol and acetaminophen
May 13, 2013 Edit: sorry for the typo in the title , can't edit I looked around on google quite a bit and it's very hard to find precise information on the...
- More from Physics Forums - Medical Sciences
More news stories
You're standing near an airport luggage carousel and your bag emerges on the conveyor belt, prompting you to spring into action. How does your brain make the shift from passively waiting to taking action when ...
Neuroscience 14 minutes ago | not rated yet | 0 |
(Medical Xpress)—Native peoples in regions where cameras are uncommon sometimes react with caution when their picture is taken. The fear that something must have been stolen from them to create the photo ...
Neuroscience 1 hour ago | 2 / 5 (1) | 0 |
In a remote fishing community in Venezuela, a lone fisherman sits on a cliff overlooking the southern Caribbean Sea. This man –– the lookout –– is responsible for directing his comrades on the water, ...
Neuroscience 3 hours ago | 4 / 5 (1) | 0 |
Many brain researchers cannot see the forest for the trees. When they use electrodes to record the activity patterns of individual neurons, the patterns often appear chaotic and difficult to interpret.
Neuroscience 5 hours ago | not rated yet | 0
(Medical Xpress)—We spend about a third of our life asleep, but why we need to do so remains a mystery. In a recent publication, researchers at University of Surrey and University College London suggest a new hypothesis, ...
Neuroscience 6 hours ago | not rated yet | 0
The level of immunity to the recently circulating H7N9 influenza virus in an urban and rural population in Vietnam is very low, according to the first population level study to examine human immunity to the virus, which was ...
1 hour ago | not rated yet | 0 |
Researchers at Emory University have identified a protein that stimulates a pair of "orphan receptors" found in the brain, solving a long-standing biological puzzle and possibly leading to future treatments for neurological ...
1 hour ago | not rated yet | 0 |
Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it's a popular treatment for older ...
38 minutes ago | not rated yet | 0 |
Prostaglandin analogues (PGAs), drugs which lower intraocular pressure, are often the first line of treatment for people with glaucoma, but their use is not without risks. PGAs have long been associated with blurred vision, ...
1 hour ago | not rated yet | 0
Youth who had a schoolmate die by suicide are significantly more likely to consider or attempt suicide, according to a study in published in CMAJ (Canadian Medical Association Journal). This effect can last 2 years or mo ...
48 minutes ago | not rated yet | 0
Most elite athletes consider doping substances "are effective" in improving performance, while recognising that they constitute cheating, can endanger health and entail the obvious risk of sanction. At the same time, the ...
48 minutes ago | not rated yet | 0