A study by Johns Hopkins scientists has revealed that
stimulating brain cell receptors for certain hormonelike
chemicals in brain cells called prostaglandins can protect
the cells from amyloid *-peptide 42, or A*1-42, a compound
that has been linked to brain cell death and Alzheimer's
disease.
Prostaglandin E2, known as PGE2, is produced via the
action of the COX-2 enzyme, which can contribute to brain
injury. In spite of the negative effects of COX-2, ongoing
studies have shown that PGE2 can actually provide some
protection against brain cell death by binding to various
PGE2 receptors.
Prostaglandins are a class of compounds that act like
hormones by binding to specific receptors. Their many
functions include constricting and relaxing blood vessels,
controlling clotting, causing pain and both increasing and
decreasing inflammation.
Because neuroinflammation is thought to play a role in
the development of Alzheimer's, PGE2 was a logical place to
look for clues to the disease's toxicity and brain cell
death, according to co-lead researcher Sylvain Doré,
an associate professor of
anesthesiology and critical care medicine and of
neuroscience at the School of Medicine.
Although it was already known that PGE2 can offer some
protection against neurotoxicity, Doré's study shows
that this protection is linked to stimulation of receptors
EP2 and EP4. This stimulation results in a cascade of
events inside brain cells that produces cyclic-AMP, or
cAMP, a molecule that protects brain cells by reducing the
toxic effects of A*1-42.
Doré speculates that the presence of A*1-42 in
neuritic plaque, a waxy translucent substance consisting of
protein and other materials, a hallmark in the brains of
Alzheimer's patients, may cause cellular death by
self-assembling into long protein filaments that are toxic
to neurons.
It's also possible, Doré said, that
prostaglandin protection works by modifying the link
between A*1-42 and the overproduction of free radicals.
Free radicals are highly reactive chemicals that oxidize
other molecules and at high concentrations lead to cell
death. Free radicals are associated with neuronal loss
observed in Alzheimer's.
"The development and testing of molecules that can
enhance PGE2 receptor activity, and further research into
how these receptors increase cAMP concentrations and
improve protection could lead to successful new
treatments," Doré said.
In the study, published in the European Journal of
Neuroscience, the researchers focused on four specific PGE2
receptors, EP1-4, in cortical neuronal cells cultured from
postnatal mice.
To establish A*1-42-induced neurotoxicity, Doré
and his team incubated these neurons with freshly dissolved
A*1-42 protein for 48 hours. The analysis of the cells
showed that A*1-42 resulted in a net increase in neuronal
cell death compared to control cells that did not receive
the peptide.
To investigate the effect of PGE2 on A*1-42 toxicity,
neurons were co-treated with A*1-42 and different
concentrations of PGE2. Results showed that PGE2
significantly increased cell survival compared to cultures
that received only A*1-42.
To determine which of the four PGE2 receptors was
responsible in the protection against A*1-42 toxicity, the
researchers conducted three separate experiments. In the
first they co-treated neurons with A*1-42 and the EP2
agonist butaprost. An agonist is a drug that mimics the
action of a natural substance and binds to that substance's
receptor. Results showed that the stimulation of EP2
receptors offered significant protection against A*1-42
neurotoxicity.
They also co-treated neurons with A*1-42 and the
EP4EP3 agonist, OHPGE1, and received similar results.
Conversely, co-treatment of the cells with the EP3EP1
agonist, sulprostone, and A*1-42 exhibited no significant
protection.
Doré's group concluded that the protective
effects against A*1-42 neurotoxicity are specific to PGE2
receptors EP2 and EP4.
The researchers next pursued changes in cAMP levels as
a potential underlying cellular mechanism in the protective
actions of EP2 and EP4 agonists. They treated neurons with
PGE2, butaprost or OHPGE1 for 15 minutes and measured the
cAMP concentration inside the cells. Results showed that
brief exposure of neurons to PGE2 almost tripled cAMP
levels, and exposure to butaprost or OHPGE1 almost doubled
them.
Subsequently, to address whether PGE2-mediated
neuroprotection involves cAMP, Dore and his group measured
neuron toxicity of A*1-42 in the absence or presence of
cAMP. Treatment with cAMP significantly enhanced cell
health after A*1-42 exposure indicating that stimulation of
PGE2 receptors EP2 and EP4 generates a cascade of events
that increases cAMP concentrations and, in turn, reduces
A*1-42 neurotoxicity.
"Due to the established link between A*1-42 and
Alzheimer's disease, this discovery could lead to better
drug therapies for treating this disease," Doré
said.
Additional researchers in this study include co-lead
author Valentina Echeverria, formerly of Hopkins, and
Andrew Clerman, a graduate student in the Department of
Anesthesiology and Critical Care Medicine.
This study was funded by grants from the National
Institutes of Health.