SIRT1 Pathways and the Prevention of Alzheimer's Pathology

A highly conserved set of genes known as the sirtuin family are known to be activated by caloric restriction (CR) and extend the lifespan of a number of species. CR may also reduce the risk of Alzheimer's Disease, and can prevent the formation of amyloid plaques in transgenic mouse models of AD. The question, then, is whether sirtuin gene activation is a mechanism through which CR can prevent AD pathology, and what genes/compounds are involved in this particular biochemical cascade. Since I'm writing this post, you can probably guess that I've found an article that addresses this very question....

This paper focuses on one particular mammalian sirtuin, SIRT1, as CR increases SIRT1 activity in brain. SIRT1 is a NAD+ dependent histone/protein deacetylase, which basically means that it requires the conversion of NAD+ to NAM in order to work, and its enzymatic activity is to deacetylate histone proteins. Both transgenic mouse models and cell culture are used to parse out the effects of SIRT1. This paper is figure-intensive so I'll just show a couple highlights.

CR is effective in decreasing the levels of toxic amyloid fragments ABeta1-40 and ABeta1-42 in transgenic mice that express mutant amyloid precursor protein


CR also shifts the NAD+/NAM ratio towards NAD+, which is favorable to increased SIRT1 activity.

Increasing NAD+ concentration reduces the amount of toxic amyloid fragments in neuronal cultures taken from transgenic mice that express mutant amyloid precursor protein (APP).


APP is normally processed by an enzyme known as alpha secretase. Cleavage of APP by beta and gamma secretase are thought to release the toxic amyloid fragments (1-40 and 1-42). Interestingly, adding NAD+ to transgenic neuronal cultures may decrease the amount of toxic amyloid by activating alpha-secretase, which cleaves APP in beneficial ways that do not form the 1-40 and 1-42 fragments.


Even more exciting is when the investigators made a mutant mouse that overexpresses SIRT1, they found that alpha secretase activity was increased.


The investigators also connected decreased Rho kinase (ROCK1) levels to increased alpha secretase activity, but I don't want to bog this post down with more graphs. Suffice to say, they were able to demonstrate that the signaling pathway for CR looks roughly like this:


There are still some weak points in this cascade, most notably being the connection between ROCK1 and alpha secretase; the paper didn't make a particularly good causal link. All in all, though, the data is strongly suggestive and ROCK1 should definitely be targeted for further investigation as it is clearly influenced by SIRT1 and at least tightly correlated with alpha secretase activity in an inverse fashion.

The take-home message:
1. CR increases SIRT1 expression and activity, which decreases "bad" amyloid by increasing the processing of APP by the "good" alpha secretase.
2. The beneficial effects can be produced by artificially inducing activation of this pathway at different points... skipping CR altogether.

The reason I like this study is because the investigators endeavoured to individually activate successive steps in the CR-induced biochemical cascade (without relying solely on the rather "dirty" manipulation of CR) in order to demonstrate causality; by systematically going down the line they were able to demonstrate the downstream effects of SIRT1 activation. While there are still a few gaps in the pathway, papers like this are what will ultimately lead to new therapeutics, and indeed a couple potential targets are to be found in this paper e.g. influencing SIRT1, ROCK1, NAD+/NAM ratios. Certainly they are worthy of exploration, instead of the current Alzheimer's drug research plans that just seems to keep focusing on producing more cholinesterase inhibitors which are of marginal effectiveness.

Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Thiyagarajan M, Macgrogan D, Rodgers JT, Puigserver P, Sadoshima J, Deng H H, Pedrini S, Gandy S, Sauve A, Pasinetti GM. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer's disease amyloid neuropathology by calorie restriction. J Biol Chem. 2006 Jun 2; [Epub ahead of print].

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"Certainly they are worthy of exploration, instead of the current Alzheimer's drug research plans that just seems to keep focusing on producing more cholinesterase inhibitors which are of marginal effectiveness."

An interesting paper, thanks for breaking it down. Although, maybe a better therapy (IMHO) would be the blockade of the improper cleavage steps rather than encouraging the proper ones (which i assume would happen anyway.) This could be achieved by blocking the gamma-secretase complex (targeting a part of the nicastrin or presenilins, etc). There's already a drug approved by the FDA for this very thing called DAPT, which works marvelously to block this cleavage step in vitro, reducing it to nearly nil. So far, I am not aware of any clinical trials in humans. As a side note, gamma secretase also processes the Notch receptor into NICD (activated Notch) which is important during development and stem cell differentiation.

I'm somewhat wary of blocking improper cleavage for precisely the reason you've stated; gamma secretase has other important functions and there may be some in the aged brain (or other organs) that we don't know yet. Combining a gamma secretase blocker would therefore put a roadblock in the way of repopulating damaged centers with the brain's own stem cells, assuming we could harness such a mechanism.

I think the better strategy would be to explore drugs that target different levels of this cascade (and potentially spill into others); certainly there are multiple widespread health benefits of caloric restriction and sirtuin activation, and it would behoove us to try and mimic as many of them as possible in one fell swoop.

I just realized that I begin a lot of sentences and clauses with "certainly". How frakkin' annoying is that?