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Researchers Reverse Cognitive Impairments in Mice with Dementia

Summary: Researchers report tau pathology can be reversed in Alzheimer’s patients with the help of a drug. Their study reveals reversing tau pathology in mouse models of dementia resulted in a reversal of cognitive deficits in spatial learning.

Source: Temple University Health System.

Reversing memory deficits and impairments in spatial learning is a major goal in the field of dementia research. A lack of knowledge about cellular pathways critical to the development of dementia, however, has stood in the way of significant clinical advance. But now, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) are breaking through that barrier. They show, for the first time in an animal model, that tau pathology – the second-most important lesion in the brain in patients with Alzheimer’s disease – can be reversed by a drug.

“We show that we can intervene after disease is established and pharmacologically rescue mice that have tau-induced memory deficits,” explained senior investigator Domenico Praticò, MD, Scott Richards North Star Foundation Chair for Alzheimer’s Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer’s Center at Temple at LKSOM. The study, published online in the journal Molecular Neurobiology, raises new hope for human patients affected by dementia.

The researchers landed on their breakthrough after discovering that inflammatory molecules known as leukotrienes are deregulated in Alzheimer’s disease and related dementias. In experiments in animals, they found that the leukotriene pathway plays an especially important role in the later stages of disease.

“At the onset of dementia, leukotrienes attempt to protect nerve cells, but over the long term, they cause damage,” Dr. Praticò said. “Having discovered this, we wanted to know whether blocking leukotrienes could reverse the damage, whether we could do something to fix memory and learning impairments in mice having already abundant tau pathology.”

To recapitulate the clinical situation of dementia in humans, in which patients are already symptomatic by the time they are diagnosed, Dr. Praticò and colleagues used specially engineered tau transgenic mice, which develop tau pathology – characterized by neurofibrillary tangles, disrupted synapses (the junctions between neurons that allow them to communicate with one another), and declines in memory and learning ability – as they age. When the animals were 12 months old, the equivalent of age 60 in humans, they were treated with zileuton, a drug that inhibits leukotriene formation by blocking the 5-lipoxygenase enzyme.

After 16 weeks of treatment, animals were administered maze tests to assess their working memory and their spatial learning memory. Compared with untreated animals, tau mice that had received zileuton performed significantly better on the tests. Their superior performance suggested a successful reversal of memory deficiency.

To determine why this happened, the researchers first analyzed leukotriene levels. They found that treated tau mice experienced a 90-percent reduction in leukotrienes compared with untreated mice. In addition, levels of phosphorylated and insoluble tau, the form of the protein that is known to directly damage synapses, were 50 percent lower in treated animals. Microscopic examination revealed vast differences in synaptic integrity between the groups of mice. Whereas untreated animals had severe synaptic deterioration, the synapses of treated tau animals were indistinguishable from those of ordinary mice without the disease.

tau protein in a cell

Compared with untreated animals, tau mice that had received zileuton performed significantly better on the tests. Their superior performance suggested a successful reversal of memory deficiency. NeuroscienceNews.com image is in the public domain.

“Inflammation was completely gone from tau mice treated with the drug,” Dr. Praticò said. “The therapy shut down inflammatory processes in the brain, allowing the tau damage to be reversed.”

The study is especially exciting because zileuton is already approved by the Food and Drug Administration for the treatment of asthma. “Leukotrienes are in the lungs and the brain, but we now know that in addition to their functional role in asthma, they also have a functional role in dementia,” Dr. Praticò explained.

“This is an old drug for a new disease,” he added. “The research could soon be translated to the clinic, to human patients with Alzheimer’s disease.”

About this neuroscience research article

Other researchers contributing to the study include Phillip F. Giannopoulos and Jian Chiu at the Alzheimer’s Center at Temple, LKSOM.

Funding: The research was funded in part by grants from The Wanda Simone Endowment for Neuroscience and the Scott Richards North Star Charitable Foundation.

Source: Jeremy Walter – Temple University Health System
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway” by Phillip F. Giannopoulos, Jian Chiu, and Domenico Praticò in Molecular Neurobiology. Published June 7 2018
doi:10.1007/s12035-018-1124-7

Cite This NeuroscienceNews.com Article
Temple University Health System “Researchers Reverse Cognitive Impairments in Mice with Dementia.” NeuroscienceNews. NeuroscienceNews, 9 June 2018.
<http://neurosciencenews.com/dementia-cognition-reversed-9301/>.
Temple University Health System (2018, June 9). Researchers Reverse Cognitive Impairments in Mice with Dementia. NeuroscienceNews. Retrieved June 9, 2018 from http://neurosciencenews.com/dementia-cognition-reversed-9301/
Temple University Health System “Researchers Reverse Cognitive Impairments in Mice with Dementia.” http://neurosciencenews.com/dementia-cognition-reversed-9301/ (accessed June 9, 2018).

Abstract

Learning Impairments, Memory Deficits, and Neuropathology in Aged Tau Transgenic Mice Are Dependent on Leukotrienes Biosynthesis: Role of the cdk5 Kinase Pathway

Previous studies showed that the leukotrienes pathway is increased in human tauopathy and that its manipulation may modulate the onset and development of the pathological phenotype of tau transgenic mice. However, whether interfering with leukotrienes biosynthesis is beneficial after the behavioral deficits and the neuropathology have fully developed in these mice is not known. To test this hypothesis, aged tau transgenic mice were randomized to receive zileuton, a specific leukotriene biosynthesis inhibitor, or vehicle starting at 12 months of age for 16 weeks and then assessed in their functional and pathological phenotype. Compared with baseline, we observed that untreated tau mice had a worsening of their memory and spatial learning. By contrast, tau mice treated with zileuton had a reversal of these deficits and behaved in an undistinguishable manner from wild-type mice. Leukotriene-inhibited tau mice had an amelioration of synaptic integrity, lower levels of neuroinflammation, and a significant reduction in tau phosphorylation and pathology, which was secondary to an involvement of the cdk5 kinase pathway. Taken together, our findings represent the first demonstration that the leukotriene biosynthesis is functionally involved at the later stages of the tau pathological phenotype and represents an ideal target with viable therapeutic potential for treating human tauopathies.

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