Fri, 06/08/2018 - 2:52pm
by 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.
"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."
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