Dementia is the second leading cause of death in Australia. Without a medical breakthrough, the number of people with dementia is expected to increase from 425,416 to 536,164 by 2025, according to Dementia Australia.
Now researchers from Lewis Katz School of Medicine at Temple University (LKSOM) in Philadelphia, USA, may have discovered that breakthrough.
One of the major goals of dementia research is reversing dementia deficits and impairments in spatial learning and, so far, a lack of knowledge in cellular pathways has been a limitation in making important clinical advances.
=Q=
However, LKSOM researchers found their breakthrough after discovering that inflammatory molecules known as leukotrienes are deregulated in Alzheimer’s disease and related conditions. They found in animal experiments that the leukotriene pathway plays an especially important role in the later stages of dementia.
When dementia begins, leukotrienes attempt to protect nerve cells. But over time, they cause damage. With this discovery, the researchers wanted to know if blocking leukotrienes could reverse the damage.
The researchers conducted a study on mice with already developed tau pathology, which is characterised by neurofibrillary tangles and disrupted synapses (junctions between neurons that enable them to communicate with each other). This results in a decline in memory and learning ability as the neurons age.
When the mice were 12 months old, which is the equivalent of age 60 in humans, they were treated with zileuton — a drug that hinders leukotriene formation by blocking the 5-lipoxygenase enzyme. After 16 weeks of treatment, the mice underwent maze tests to assess their working memory and their spatial learning memory. The tau mice that had received zileuton performed significantly better on the tests compared to the untreated mice. This suggested a successful reversal of memory deficiency in the treated mice.
To understand this process, the researchers first analysed leukotriene levels. They found that treated tau mice experienced a 90 per cent reduction in leukotrienes compared with untreated mice. They also found that the levels of phosphorylated and insoluble tau — form of protein known to directly damage synapses — were 50 per cent lower in treated animals. Microscopic examination revealed that untreated animals had severe synaptic deterioration, but the synapses of treated tau animals were no different than those of ordinary mice without the disease.
The findings of this study are exciting because zileuton is already approved by the Food and Drug Administration for the treatment of asthma. Leukotrienes are in our lungs and our brain. And now we know that, in addition to the functional role it plays in asthma, leukotrienes also have a functional role in dementia.
The researchers are now looking to translate this study to human patients with Alzheimer’s disease.
Source: Molecular Neurobiology
