Have your doctor followup on this to see about stopping
your 33% chance of getting dementia post-stroke?
Somehow I missed the report on aspirin for preventing Alzheimers.
http://www.biosciencetechnology.com/news/2014/12/blocking-receptor-brain%E2%80%99s-immune-cells-counters-alzheimer%E2%80%99s-mice?
The mass die-off of nerve cells in the brains of people with
Alzheimer’s disease may largely occur because an entirely different
class of brain cells, called microglia, begin to fall down on the job,
according to a new study by researchers at the Stanford University
School of Medicine.
The researchers found that, in mice, blocking the action of a
single molecule on the surface of microglia restored the cells’ ability
to get the job done— and reversed memory loss and myriad other
Alzheimer’s-like features in the animals.
The study, published online in The Journal of Clinical Investigation,
illustrates the importance of microglia and could lead to new ways of
warding off the onset of Alzheimer’s disease, which is predicted to
afflict 15 million people by mid-century unless some form of cure or
prevention is found. The study also may help explain an intriguing
association between aspirin and reduced rates of Alzheimer’s.
Microglia, which constitute about 10-15 percent of all the cells in
the brain, actually resemble immune cells considerably more than they
do nerve cells.
“Microglia are the brain’s beat cops,” said Katrin Andreasson,
professor of neurology and neurological sciences and the study’s senior
author. “Our experiments show that keeping them on the right track
counters memory loss and preserves healthy brain physiology.”
Implicated: a single molecule
A microglial cell serves as a front-line sentry, monitoring its
surroundings for suspicious activities and materials by probing its
local environment. If it spots trouble, it releases substances that
recruit other microglia to the scene, said Andreasson. Microglia are
tough cops, protecting the brain against invading bacteria and viruses
by gobbling them up. They are adept at calming things down, too,
clamping down on inflammation if it gets out of hand. They also work as
garbage collectors, chewing up dead cells and molecular debris strewn
among living cells— including clusters of a protein called A-beta,
notorious for aggregating into gummy deposits called Alzheimer’s
plaques, the disease’s hallmark anatomical feature.
A-beta, produced throughout the body, is as natural as it is
ubiquitous. But when it clumps into soluble clusters consisting of a few
molecules, it’s highly toxic to nerve cells. These clusters are
believed to play a substantial role in causing Alzheimer’s.
“The microglia are supposed to be, from the get-go, constantly
clearing A-beta, as well as keeping a lid on inflammation,” Andreasson
said. “If they lose their ability to function, things get out of
control. A-beta builds up in the brain, inducing toxic inflammation.”
The Stanford study provides strong evidence that this deterioration
in microglial function is driven, in large part, by the heightened
signaling activity of a single molecule that sits on the surface of
microglial and nerve cells. Previous work in Andreasson’s lab and other
labs has shown that this molecule, a receptor protein called EP2, has a
strong potential to cause inflammation when activated by binding to a
substance called prostaglandin E2, or PGE2.
“We’d previously observed that if we bioengineered mice so their
brain cells lacked this receptor, there was a huge reduction in
inflammatory activity in the brain,” she said. But they didn’t know
whether nerve cells or microglia were responsible for that inflammatory
activity, or what its precise consequences were. So they determined to
find out.
Blocking receptor preserves memory
The experiments began in a dish. Isolating viable microglia from
the brain is quite difficult. But it’s easy to harvest large numbers of
their close cousins, immune cells called macrophages. These cells
circulate throughout the body and can be readily obtained from a blood
sample. While not carbon copies of one another, microglia and
macrophages share numerous genetic, biochemical and behavioral features.
When placed in a dish with soluble A-beta clusters, macrophages
drawn from young mice responded calmly, producing recruiting chemicals
and not ramping up production of inflammatory molecules. Notably, the
output of A-beta-chewing enzymes in these young cells was robust. But
macrophages from older mice acted differently: A-beta’s presence incited
a big increase in EP2 activity in these cells, resulting in amped-up
output of inflammatory molecules and reduced generation of recruiting
chemicals and A-beta-digesting enzymes.
This early hint that age-related changes in EP2 action in microglia
might be promoting some of the neuropathological features implicated in
Alzheimer’s was borne out in subsequent experiments for which
Andreasson’s team used mice genetically predisposed to get the mouse
equivalent of Alzheimer’s, as well as otherwise normal mice into whose
brains the scientists injected either A-beta or a control solution. In
both groups of mice, the expected deleterious effects on memory and
learning didn’t arise if EP2 within microglial cells was absent, as a
result of a genetic manipulation. Blocking microglial EP2 activity
significantly improved these animals’ performance on two kinds of
standard memory tests: one that assesses how quickly a mouse forgets
that it has encountered an object before, and another that rates the
mouse’s ability to remember where a food reward is in a maze.
Looking beyond aspirin
Clearly, knocking out EP2 action in A-beta-provoked microglia
benefited memory in mice that had either gradually (the “Alzheimer’s”
mice) or suddenly (the brain-injected mice) acquired excessive A-beta in
their brains. Likewise, mouse microglia bioengineered to lack EP2
vastly outperformed unaltered microglia, in A-beta-challenged brains, at
such critical tasks as secreting recruiting chemicals and factors
beneficial to nerve cells and in producing inflammation-countering,
rather than inflammation-spurring, proteins.
Epidemiological reports suggest that the use of nonsteroidal
anti-inflammatory drugs, such as aspirin, can prevent the onset of
Alzheimer’s— although only if their use is initiated well before any
signs of the disorder begin to show up in older people, Andreasson said.
“Once you have any whiff of memory loss, these drugs have no effect,”
she said. NSAIDs’ mainly act by blocking two enzymes called COX-1 and
COX-2; these enzymes create a molecule that can be converted to several
different substances, including PGE2 — the hormone-like chemical that
triggers EP2 action.
Although PGE2 is known to regulate inflammatory changes in the
brain, it exercises diverse, useful functions in different tissues
throughout the body, from influencing blood pressure to inducing labor.
Complicating matters, PGE2 is just one of five different prostaglandins
originating from the precursor molecule produced by COX-1 and COX-2. So
aspirin and other COX-1- and COX-2-inhibiting drugs may have myriad
effects, not all of them beneficial. It may turn out that a compound
blocking only EP2 activity on microglial cells, or some downstream
consequences within microglial cells, would be better-suited for fending
off Alzheimer’s without side effects, said Andreasson. Meanwhile, her
group is exploring the biological mechanisms via which PE2 signaling
pushes microglia over to the dark side.
