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May 17, 2010
The Memory Goes Because. . .the Acetyl Groups Go?
Posted by Derek
I've been meaning to write about this paper from a recent issue of Science. They've been studying the differences between young (3-month) mice and old (16-month) mice - their ability to learn, and to remember. Markers of neuronal plasticity and the like are pretty similar between the groups, although the older mice definitely show some impairments in spatial learning and recall. Looking down at the genetic level, for effects on chromatin handling, didn't seem to show much, either - the young and old mice have similar levels of histone deacetylase and histone acyltransferase enzymes.
But a look at the real levels of acetylated histones showed something different: the older mice seemed to be deficient in one particular type of acetylation, H4K12. That particular lysine residue was acetylated much more readily in the younger animals in response to a fearful event, but the older animals didn't upregulate the process. A broad-based search using microarrays showed that a wide range of genes were regulated by the young mice when learning to avoid a fear stimulus, but were not altered to nearly the same degree in the older ones. And as it turns out, the H4K12 acetylation looks to be one of the common factors in the regulation of these genes.
The authors went so far as to use Vorinostat (SAHA), a marketed histone deacetylase inhibitor, to test this hypothesis. Administering that to the older mice (directly into the brain; it doesn't really cross on its own) led to both H4K12 effects and to beneficial effects on learning.
This is a long way from being a therapy, but it's a very interesting lead towards one. The effects of messing around with histone acylation states could be profound (both in the sense of "profoundly good" as well as "profoundly bad"), so it's going to be quite a while before the dust settles enough for us to know what to do. But I'm encouraged to see things like this coming up. Given that I'm 48, we're going to have to keep moving right along in order to have something ready by the time I'm going to need it!
Comments (13)
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1. lynn on May 17, 2010 11:07 AM writes...
Very interesting... but maybe getting over fear responses is part of growing up. And wow what specificity would be required for this sort of thing to be practical by the time you need it [too late for me]!
Permalink to Comment2. REtread on May 17, 2010 11:51 AM writes...
You really should take rodent work on cognition with a large shaker of salt. A recent post described knockout mice for a gene called Pals1. They have no cerebral cortex at all yet they are viable and able to eat and reproduce. Humans missing even parts of their cortex aren't this lucky. The link -- http://luysii.wordpress.com/2010/05/07/is-this-brain-necessary/
Permalink to Comment3. retread on May 17, 2010 11:58 AM writes...
Rodent work on cognition should be taken with a large dose of salt. A recent post describes mice lacking a gene called Pals1 (made by the knockout technique). Despite lacking any cerebral cortex at all, the animals are viable and able to eat and breed. Humans lacking even part of their cerebral cortex aren't nearly so lucky. The link http://luysii.wordpress.com/2010/05/07/is-this-brain-necessary/
Permalink to Comment4. partial agonist on May 17, 2010 12:57 PM writes...
One problem is assusing that SAHA's effects have only to do with its HDAC activity. As memory serves, it is merely a micromolar HDAC inhibitor. Given its structure (a lipophilic floppy hydroxamic acid, google 'Vorinostat wiki') there are lots of metalloprotaeases it might also hit. Maybe selectivity data for SAHA is known, though. It seems to me like it would be a little dirty.
Permalink to Comment5. Anonymous on May 17, 2010 1:33 PM writes...
we're going to have to keep moving right along in order to have something ready by the time I'm going to need it!
You mean you don't want a direct injection straight through your skull?
Permalink to Comment6. milkshake on May 17, 2010 1:38 PM writes...
only 48? You look much more ...experienced.
This reminds me an old joke about a physician explaining to a patient: "unfortunately your lung carcinoma progressed to a point that you would not benefit from surgery. Also, the latest test results suggest that you suffer from Alzheimer."
Patient: "that's good - at least I don't have a cancer."
Permalink to Comment7. nucleophile on May 17, 2010 5:28 PM writes...
I thought Derek Lowe was only 36 years old. In addition other details are also incorrect since Derek Lowe was born in Dearborne, Michigan, has a middle initial of "C" not "B", and does not have the time to run a pharmaceutical blog. :)
Permalink to Comment8. The Pharmacepidemiologist on May 17, 2010 9:05 PM writes...
The same thing happened with clioquinol in the lab, but the Phase 2 was a bust.
Permalink to Comment9. Response to Milkshake on May 17, 2010 9:07 PM writes...
The way I heard it was: What's the upside to Alzheimer's disease? You make new friends every day.
Permalink to Comment10. Homer on May 18, 2010 2:36 AM writes...
The outcomes of the SAMPL Challenge will be interesting in this regard.
J Biomol Screen.2009; 14: 1245-1250
http://jbx.sagepub.com/cgi/content/abstract/14/10/1245
You might want to blog about the winners and losers at the end of the challenge.
Permalink to Comment11. KG on May 18, 2010 11:30 PM writes...
SAHA is a reasonable inhibitor of the HDAC class, with an IC50 of a few hundred nM. It's a pan inhibitor of the class, but not terribly dirty (not anomalously so, anyway) otherwise.
Permalink to Comment12. KG on May 18, 2010 11:36 PM writes...
It's also worth nothing that the relationship between aging and HDAC has already been observed in the literature, e.g. see:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748411/
or
http://www.jneurosci.org/cgi/content/short/27/23/6128
or
http://www.nature.com/nrn/journal/v10/n7/full/nrn2660.html
Permalink to Comment13. Glen on May 28, 2010 11:00 AM writes...
I cringe every time I read about neurotrophics. Under normal circumstances plasticity is a zero sum game. The hebbian maximum (allowing for short term variance) is established prior to the up-regulation of KCC2 via GDPs. Any increase in plasticty in well differentiated neurons will come at the expense of prior morphology of said.
That being said, if you want a HDAC inhibitor that does not require drilling holes in heads, sodium butyrate will cross the BBB IIRC.
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