[ExI] Jaw-dropping CWRU Alzheimer's breakthrough?

[spike]

Finally an article with at least a little technical detail.  The
long-prevailing model for age-related brain degradation counter-indicated
bexarotene, but the test results were a surprise.  Check out the last two
paragraphs below.

 

 

http://www.bioworld.com/content/eisai-lymphoma-drug-reverses-alzheimers-dise
ase-symptoms-0

 

 

Eisai Lymphoma Drug Reverses Alzheimer's Disease Symptoms

By Anette Breindl
Science Editor

Researchers identified a drug which, in animals, rapidly decreases both
plaque area and soluble amyloid beta levels in mouse models of Alzheimer's
disease. And it's FDA-approved.

The drug in question is Targretin (bexarotene, Eisai Inc.) which was
approved for the treatment of cutaneous T-cell lymphoma in 2000.

Gary Landreth told BioWorld Today that "our results on plaque clearance are
unprecedented." In mice treated with Targretin, plaque levels declined by
more than 50 percent within three days, and ultimately declined by more than
75 percent.

"We were stunned," he added, "and it took quite a while for us to believe
our own data. The speed is shocking." Landreth is a professor of
neuroscience at Case Western Reserve University School of Medicine and the
senior author of the paper describing those data, which was published in the
Feb. 9, 2012, advance online issue of Science.

Landreth and his team decided to test Targretin in Alzheimer's mice because
it affects the retinoic X receptor. That receptor, in conjunction with two
other proteins, controls brain levels of apolipoprotein E, or ApoE, which,
in turn, is the protein that clears amyloid beta. That protein is
overproduced in Alzheimer's disease, and the amyloid plaques it forms are
the anatomical calling card of the disease - those plaques also were once
thought to be the cause of the memory problems that are its behavioral
calling card.

As several drugs targeting amyloid plaques have failed in late-stage
clinical trials, it has become clear that plaques themselves are not overly
harmful, and they may even be protective against what many now consider the
real villain: soluble amyloid beta, especially so-called oligomers.

Targretin, Landreth said, "targets both soluble amyloid beta and plaque.
[It] drives up ApoE expression in astrocytes, which clears soluble Abeta,
and this likely improves cognition." But it also "provokes the change in
activation state of microglia and reanimates their phagocytic machinery, and
this is responsible for plaque clearance."

When Landreth and his team treated several different mouse models of
Alzheimer's disease with Targretin, levels of soluble amyloid beta decreased
within six hours. The team tested their mice on several learning tasks; in
some of those tasks, they saw improvements with as little as one week of
treatment, though in others, longer treatment was necessary. The drug also
improved the animals' olfactory abilities, which are normally impaired by
plaque deposition. Finally, animals that had lost the ability to build nests
- a social behavior for mice - were once again able to do so after Targretin
treatment.

Although he has no solid proof, Landreth's hunch is that the drug's
effectiveness at improving behavioral symptoms is in large part due to its
effects on soluble amyloid beta, not plaques. "I think that as we pull down
Abeta levels, synaptic function improves, and that subserves the improvement
in behavior," he said.

Landreth stressed that the results are as yet preclinical, and that the
model his team used is unable in principle to give any clues to how
Targretin will affect individuals with advanced Alzheimer's. The reason, he
said, is that in mouse models of Alzheimer's disease, "the neurons don't
die, and that is a serious problem for extrapolating to later stages of the
disease."

Still, he said, his team's results showed that, in animals, "early in the
disease the effects . . . are largely reversible."

And on the plus side, because Targretin is an approved drug, "we have just
cut 10 years off of the developmental timeline." That doesn't mean he's not
in a big hurry to get started. "I want to be in the clinic with this within
the next two months," he said.

Given the known, albeit indirect, connection from the retinoic acid receptor
to ApoE levels and, from there, to amyloid, in hindsight the notion of
trying to treat Alzheimer's disease with Targretin might seem obvious enough
to be tested a long time ago. But Landreth said, a priori, there were also a
number of reasons to suspect that such an approach would fail.

Specifically, he said, "one might have predicted a boatload of side
effects," since the retinoic X receptor "works in coordination with a number
of other receptors." That those side effects did not occur "is just
serendipitous."

 

 

 

 

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