
Chemical clears Alzheimer's protein and restores memory in mice - coris47
http://www.nature.com/ncomms/2015/151208/ncomms9997/full/ncomms9997.html
======
blisterpeanuts
This is heartening news; if not a cure, at least it suggests a promising
avenue for future research into this terrible condition.

This LiveScience[1] article is an easily read summary that also mentions a
critique of the approach.

Given the unfortunate history[2][3] of falsified Korean scientific research,
it would be prudent to withhold judgment until these results have been
reproduced in other labs around the world.

1\. [http://www.livescience.com/53019-epps-chemical-washes-
away-a...](http://www.livescience.com/53019-epps-chemical-washes-away-
alzheimers-plaque.html)

2\.
[http://www.nytimes.com/2009/10/27/world/asia/27clone.html?_r...](http://www.nytimes.com/2009/10/27/world/asia/27clone.html?_r=0)

3\. [https://www.washingtonpost.com/news/to-your-
health/wp/2015/0...](https://www.washingtonpost.com/news/to-your-
health/wp/2015/07/01/researcher-who-spiked-rabbit-blood-to-fake-hiv-vaccine-
results-slapped-with-rare-prison-sentence/)

~~~
wobbleblob
Ever since a family member was diagnosed with Alzheimer's, I've been paying
attention to reports like these. Every other year, there is a paper about a
major breakthrough, and surely a cure should be just around the corner any
time now.

Every few years there is a paper that claims that we now finally know what
causes the disease, and every time it's something different, and every time
you never hear of a followup.

It's about 3 decades later now, and as far as I can tell, there is still no
actual progress in the way of treatment. An alzheimer's diagnosis still means
the same as it did in the 80's or in the 60's for that matter.

About this cure that is just around the corner. It came too late for my
grandparents generation, it came too late for my parents' generation, it came
too late for my generation, I wouldn't be surprised if it came too late for my
children's generation. I don't believe in it any more.

~~~
CamperBob2
When you realize that pretty much _every_ disease and condition has similar
papers written about it, you start to realize that the way we do medical
research is pretty messed up.

Keep in mind that they still haven't really decided whether salt is bad for
you or not, or what the real effects of dietary cholesterol are. Widespread
conditions that should be much easier to research and understand than
Alzheimer's are still very controversial.

~~~
CWuestefeld
_you start to realize that the way we do medical research is pretty messed
up._

The way the media reports on research (not just medical) is really messed up.

~~~
CamperBob2
Both are true, IMHO, again returning to the dietary salt/cholesterol example.
It is easy to point to peer-reviewed literature that backs up any point of
view you want to take.

The scientific community needs to get its own act together before criticizing
the popular media. Few other scientific disciplines are less reliable than
medical research, and even fewer are more important.

------
andy_ppp
Wow, you can buy some EPPS (the chemical in the article) here for £39.20?

[http://www.sigmaaldrich.com/catalog/product/sigma/54465?lang...](http://www.sigmaaldrich.com/catalog/product/sigma/54465?lang=en&region=GB)

Looks interesting research but I'm sure this stuff probably can't be that good
for you!

~~~
toabi
Shows 137.50€ here :D

~~~
slight
143.50€ here... (Spain).

~~~
codecamper
158 euro here. (Morocco) maybe a pricing algorithm that increases price based
on demand?

~~~
PythonicAlpha
Or based on the existence of positive research papers ;)

------
reasonattlm
If you go digging around you'll find dozens of other similar results in the
past five to ten years for dozens of various compounds, some of which produce
larger effect sizes than this one. This is nothing to get excited over.

It is interesting the way in which various groups leap upon some research
reports but not others. The challenge is always having the context for the
broader state of research to understand whether it is meaningful or new or
not.

The present mainstream view of Alzheimer's is that amyloid (and tau) clearance
is the way to go. Immunotherapies are the most developed tool, but that is so
far proving to be hard - it is too early to say whether failures in clinical
trials are because it is hard or because amyloid clearance isn't as useful as
thought in this condition. Which could be for any number of reasons including
that amyloid-related biochemistry is the problem, but clearing a particular
variant or stage of its aggregation doesn't touch that problem area.

Amyloid levels in the brain are in fact highly dynamic on a very short
timescale. That Alzheimer's develops slowly supports the view that the
condition is a slow degeneration of natural clearance mechanisms, such as the
filtration performed by the choroid plexus, or the more recently investigated
peristaltic passage of fluid out of the brain by other channels. E.g.:

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245362/](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245362/)

On that latter point, the Methuselah Foundation just a few days ago seed
funded a startup company that will investigate whether reversing the
degeneration of peristaltic fluid passage with aging will improve clearance
and thus stop the progression of Alzheimer's. It's based on as yet unpublished
work by Doug Ethell at GCBS Western who presented at Rejuvenation
Biotechnology 2015 (
[http://www.sens.org/files/conferences/rb2015/RB2015-Program....](http://www.sens.org/files/conferences/rb2015/RB2015-Program.pdf)
), and has the merit that it should be a fast failure if the theory is wrong,
unlike many of the other efforts in Alzheimer's research.

~~~
zepn
Just because I agree with most of your points and there seem to be some
overexcited responses to the OP, here are two papers for anyone interested,
summarising Aβ and tau [0] and some failures of Aβ therapies [1].

[0]
[http://www.nature.com/nrn/journal/v12/n2/abs/nrn2967.html](http://www.nature.com/nrn/journal/v12/n2/abs/nrn2967.html)
[1]
[http://www.nature.com/nrneurol/journal/v9/n12/full/nrneurol....](http://www.nature.com/nrneurol/journal/v9/n12/full/nrneurol.2013.223.html)

------
eveningcoffee
The title is "EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1
mice by disaggregation of amyloid-β oligomers and plaques" and it does not say
that it reduces memory, it says _" EPPS reduces Aβ-aggregate-induced memory
deficits in mice"_ but they also say that _" We observed substantial rescue of
working memory deficits in Aβ-infused mice by EPPS treatment"_.

Of course this is only small part of the paper and I have no training to
appreciate it more.

~~~
Brakenshire
I'm not an expert either, but as far I can see:

The diagramme showing how much memory is recovered is figure one. White is
before the administration of the "Alzheimer's protein" (AB protein), black is
without the new clearing chemical, blue is with it, and then the different
blue columns showing different concentrations. Fig 1c is prophylactic
treatment (clearing molecule administered before, during and after the AB
protein), Fig 1d is clearing molecule administered alongside AB protein. The
impairment seems to more or less recover fully back up to where it was
originally, in all four combinations of timing and clearing molecule
concentration.

But bear in mind:

* The mouse model for Alzheimer's seems to be very, very simplified - as far as I can see they literally inject big doses of these proteins directly into the brain in order to induce Alzheimer's like symptoms, that doesn't mean this is equivalent at all to the complex chemical processes underlying Alzheimer's. AB proteins are observed in Alzheimer's patients, but they are also observed in healthy patients, and other proteins are also seen in Alzheimer's patients, some of which are recently thought more likely to be the underlying driver of the disease.

* All of this occurs over a very short period of time. Someone who has developed symptoms of Alzheimer's will have had the disease process occurring for many years beforehand. Recovery a few days after administration of the protein doesn't mean that damage would be recoverable years later.

Edit: I'm actually just looking at the first experiment, they also do longer
term trials with a mouse model which has been genetically altered to over-
expresses the AB protein. Arguably this is still a very over-simplified model,
but it does more to address the time question. They say Alzheimer's symptoms
usually develop at 5 months, then they administer the clearing molecule at
10.5 months for 3 months. Those experiments shows about half the deficit being
recovered relative to normal age-matched mice.

------
plg
it's a great day for mouse health

~~~
wiremine
You say that tongue in cheek, but as a non-scientist, I've always wondered how
much "mouse science" ultimately translates to humans. My guess is it's very
low, but knowing a percentage would help me better understand how to proceed
reports like this.

~~~
pbnjay
Mice are ~30% similar genetically to humans, so a surprising amount of
transfers. Rats are a bit more similar IIRC, but mice breed quicker so it's
easier to do bigger studies...

Source: Used to work in mouse research on addiction (alcohol, cocaine,
nicotine, etc).

Edit: This link gives even more specifics on the similarity:
[https://www.genome.gov/10001345](https://www.genome.gov/10001345) \-- 30% is
probably accurate, but in terms of function, it's even higher.

~~~
sliverstorm
30% similar? Didn't we find that bananas share 50% of genes with humans?

~~~
plg
that would explain a lot

------
nashashmi
I am having an epiphany. Maybe this "Alzheimer protein" is supposed to be the
brain's defenses to something much worse. Maybe this protein is a "reaction"
similar to skin rashes when it absorbs poison ivy's urisol.

If Alzheimer was simply a deficiency of nutrients, I wouldn't think this way,
but if it really is a protein that "can be cleared", why did it get there in
the first place?

~~~
jupp0r
I'm not an expert, but human lifespans have only risen to relevant heights
very recently. It's simply not enough time for it for evolution to kick in.

~~~
jonnathanson
Average life expectancy is a commonly misunderstood (and widely
misrepresented) concept. We hear things like "Humans really only lived into
their 40s in the Stone Age," or what have you. This is untrue.

 _Average_ (arithmetic mean) life expectancy was a lot lower because it was
heavily skewed by infant mortality. Up until very recently, many more babies
died within their first few years of life. We've dramatically improved our
ability to produce and distribute food and medicine, which has had a profound
effect on infant survivability. But we haven't actually lengthened the average
life expectancy of an adult who survives the first few years of childhood by
all that much.

Point is, plenty of people have been living into their 70s, 80s, and 90s for
as long as we've existed as a species. That said, the prevalance of diseases
like Alzheimer's might be a fairly modern aberration, perhaps owing to
lifestyle, environmental, and dietary factors.

~~~
daveguy
"That said, the prevalance of diseases like Alzheimer's might be a fairly
modern aberration, perhaps owing to lifestyle, environmental, and dietary
factors."

Also somewhat owing to the recognition of Alzheimer's as a disease state
(coincident with amyloid beta plaques) rather than just part of "getting old".
The difference between "more prevalent" and "better identified" is difficult
to determine.

~~~
jonnathanson
That's a totally fair point.

------
midnitewarrior
Wow, they've prevented Alzheimer's in healthy mice, and restored memory
function to sick Alzheimer's affected mice. The treatment is non-toxic at
ridiculous levels too.

------
keeptrying
There have been at least 3 previous solutions for AD in mice which have never
panned out in humans.

~~~
brwnll
Source?

~~~
pcrh
Actually its more like 300 treatments that haven't panned-out...

‘Too much good news’ – are Alzheimer mouse models trying to tell us how to
prevent, not cure, Alzheimer’s disease?

[https://www.ncbi.nlm.nih.gov/pubmed/?term=20542579](https://www.ncbi.nlm.nih.gov/pubmed/?term=20542579)

------
daveguy
I would like to point out that the main study described in this article is not
the "inject aggregated amyloid beta fibrils" that is described first. That
study was a preliminary study that prompted the main study which uses
genetically altered mice.

The test for alzheimers for the first study (previously reported but
summarized again) was to quantify how much the mice deviates from solving a
maze that they have been trained to solve.

In the first they injected amyloid beta aggregates into mouse brains and found
that EPPS administered orally at 30 mg/kg and 100 mg/kg restores the ability
of the mice to efficiently solve the maze.

Next they tested toxicity quantified the amount of EPPS that passes the
brain/blood barrier. For toxicity they found no signs of toxicity at 2000 mg /
kg (20x dosage). For blood/brain barrier, as you go up in blood concentration
you should go up in brain concentration if there is a good penetration from
blood to brain. If the barrier is high then you immediately get high blood and
low brain concentrations. The point where there is no longer a significant
increase in brain concentration when increasing blood concentration is used to
determine effective dosage concentrations. They found that at 100 mg/kg they
were starting to see increased blood/brain ratios so they targeted 10-100
mg/kg for the next study.

 _MAIN STUDY_ (which included identifying the dosage level) used mice that
were engineered to "get Alzheimer's" starting around 5 months of age because
they produce a human gene (transgenic) that is a precursor to form the AB
plaques. This transgenic model is established and the mice showed the expected
amyloid beta plaques and had difficulty solving the maze at 10.5 months as
expected.

Starting at 10.5 months they gave oral doses of EPPS at 10 mg/kg and 30 mg/kg
and monitored maze solving along with several additional tests: likelihood to
freeze when presented with negative input (fear conditioning) and ability to
find hidden platforms when swimming (water maze). Both tests improved
significantly to the wild-type (no Alzheimer's) level when taking EPPS. They
also did dose dependency at .1 1 and 10 mg/kg. There was a steady improvement
at higher doses.

They also took slices of the mouse brain and tested whether or not the neurons
responded differently to electrical stimulation. They found no difference in
wild-type (WT, non-genetically altered) or transgenic (TG, altered) response
to electrical stimulation with and without EPPS. This hints at no difference
in neural activity with or without EPPS. They also gave EPPS to WT for the
behavioral tests and did not see a difference (although that was not shown in
the behavioral test figures).

They also took slices of the brain and stained them with a fluorescent dye to
show the Alzheimer's associated plaques. There is a significant quantifiable
reduction in plaques in the treated mice.

They used several other techniques to confirm that they were actually AB
plaques and they disaggregated by a specific site of activity. I won't go into
those specifics, but to say that this was a VERY well designed and executed
study across multiple lines of inquiry and all of the lines of inquiry point
to the same conclusion:

EPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by
disaggregation of amyloid-b oligomers and plaques

And that's why it's a Nature article.

~~~
DenisM
Excellent summary for those of us without enough will or ability to read the
original article. Thank you, good sir.

------
aantix
A slightly unrelated question; are there any companies out there that are
working on a replacement for mouse models in disease research?

I'm think more in terms of computer simulation?

~~~
bosdev
Yes, but it's incredibly complicated.

------
openbsdway
Perhaps Pinky can now stop asking Brain what it is they will be doing tonight!

------
antidaily
BUT it makes for pet chimpanzee super smart and and ruins human civilization,
setting up en epic battle between apes and men.

------
heimatau
Ginkgo Biloba [1] is very solid at helping preventing Alzheimer's, even in
some cases slowing it down when it's already occurring. Lots of research on
the benefits of Ginkgo. Yet most don't know about it.

[1]
[https://duckduckgo.com/?q=ginkgo+biloba+alzheimer+site%3A.ed...](https://duckduckgo.com/?q=ginkgo+biloba+alzheimer+site%3A.edu+OR+site%3A.gov)

~~~
lg
[https://nccih.nih.gov/research/results/gems](https://nccih.nih.gov/research/results/gems)

~~~
pbnjay
Quotes to save the clicks...

> The dietary supplement Ginkgo biloba was found to be ineffective in reducing
> the development of dementia and Alzheimer’s disease in older people

> The GEM study—the largest of its kind to date—was a randomized, double-
> blind, placebo-controlled clinical trial of 3,069 community-dwelling adults
> aged 72 to 96,

> Compared with placebo, ginkgo did not lessen cognitive decline. Researchers
> found no evidence of an effect on cognitive decline in general, or on
> memory, attention, visual-spatial construction, language, or executive
> functions. There were no differences by age, sex, race, education, or
> baseline cognitive status.

