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

Jeff Davis jrd1415 at gmail.com
Thu Mar 15 21:02:46 UTC 2012

On Wed, Mar 14, 2012 at 9:09 PM, spike <spike66 at att.net> wrote:

>...we have a notion that bex somehow stimulates the mechanism which cleans up beta amyloids, but it isn't a good barrier crosser, but other similar medications are good crossers.

In several of your postings, Spike, you have mentioned that bex "isn't
a good barrier crosser".  These multiple assertions are liable to
cause folks to accept it as fact.  (Which it very well might be; links
please.)  However, before that claim matures into solid belief, I have
a couple of questions:

In the CWRU research, the mice were administered bex, and it "worked".
 So one might well ask, "If bex crosses the BBB only poorly, how come
it worked?"

One possible answer would be:  "The word "poorly" is seriously
imprecise.  Poorly relevant to what?  Clearly in the CWRU research,
poorly did NOT mean too poorly to be effective.  In terms of
effectiveness, there was no poorly to it.

We need to get at real numbers here, because if it "worked" in the
mouse model, then either "poorly" is still good enough, or bex's
effectiveness in the brain is not a function of its BBB crossing
ability.  In this latter regard I am reminded of this comment about
bex from the Wikipedia article:
Bexarotene is a retinoid specifically selective for retinoid X
receptors [RxRs]...
RXRs are located primarily in visceral organs such as the liver and kidney.

Liver and kidneys.

Since the current "theory" (as I understand it, of course) is that bex
upregulates ApoE, and that the Beta-Amyloid clearance follows, one
might ask, "Does ApoE usher from the liver and kidneys, and from there
proceed to the brain, crossing the BBB to perform its cleanup? In
which case it is ApoE's BBB crossing ability that is crucial -- and
apparently sufficient -- not bex's.

And a related question:  The CWRU research indicated that the
"cleanup" included reduction of soluble Beta-amyloid by 25% in a six
hour period.

Now, I haven't read the original research paper, so I may need someone
who has to help me here.  What I want to know is: were the soluble
beta-amyloid levels that were measured as having been reduced by 25%
measured in (1) blood, (2) body-wide blood and cytoplasm, or (3) brain
cell cytoplasm?

If the reduced amyloid levels are body-wide levels, then any reduction
in soluble amyloid levels in the brain could logically be the natural
result of equilibration of plasma amyloid levels body-wide by

Finally, plaque digestion in the brain has to be on site, as the
plaques are immobile.  If ApoE is the agent of plaque digestion then
ApoE must either cross the BBB or originate -- by up-regulation
presumably -- on the other side of the BBB.

Just trying to keep this all straight.

Best, Jeff Davis

   "Everything's hard till you know how to do it."
                        Ray Charles

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