Following up on Leptin

Pure Pedantry found this paper on leptin's effects in the hippocampus, and then went on to wonder

I have never heard of a link between leptin and memory. They also make this link between ABeta mice and leptin. ABeta is a protein whose accumulation has been linked to Alzheimer's. Mice that create to much ABeta show cognitive deficits. They show that an ABeta overproducing mouse also showed improvement when treated with leptin -- and link that result to the observation that leptin decreases ABeta. I am not sure what to make of that, but there is probably a metabolic story related to ABeta production.

Since he is lucky enough to have a fellow Seed blogger who currently works with AD transgenic mice, I wanted to expand on his thoughts a bit.

Leptin can mitigate increases in brain amyloid load a couple of ways. Firstly, it can decrease the amount of amyloid produced by reducing the activity of an enzyme called beta-secretase, which cleaves amyloid free from its precursor protein. Secondly, leptin can modulate the uptake of Abeta protein by apoE and thus reduce extracellular levels of the protein. Which is especially good because Abeta is thought to form fibrils that muck up synapses when just floating around in the brain (the formation of plaques may in fact be the result of a clearance mechanism). Leptin might also enhance cognition generally by altering the composition of lipid rafts in a manner conducive to molecular trafficking and synaptic transmission.

The paper PP cited was interesting because it clearly showed a bimodal relationship between leptin and cognitive performance. Going back to the amyloid/Alzheimer's Disease (AD) story, the preliminary evidence suggests that leptin may be a potential therapeutic for the treatment of AD, but I have to speculate that the dose response curve may shift a bit-- what is acceptable for a "successfully aging" individual may actually have deletorious consequences for AD patients if they are already compromised. Plus, leptin has been implicated in various inflammatory processes so there is the possibility that disease progression may actually be enhanced.

Nice find, PP!

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Thanks for the additional information but I have a few questions.
I am curious since it was mentioned that Diabetes makes the BBB resistant to Leptin do you think that being diabetic would increase your risk for Alzheimers?

I also recall from a few years back reading that inflammarion may play a role in the development of Alzheimers is that why you suggest that using Leptin as a treatment would exacerbate the disease? I have not heard anything recently and I am not sure if that is still considered a possibility.

Lastly do you know how being diabetic makes the BBB resistant to Leptin? Does it block a receptor or make the molecule to large to pass through? I have taken some neuroscience classes but I have never heard of the BBB becoming resistant.


I don't know the answer the other two, but the answer to the first question is still debated. I have read studies that say yes and studies that say no. The issue is that there are other kinds of dementias besides Alzheimer's disease -- such as vascular dementia which is basically lots of ministrokes.

We know that diabetes is definitely a risk factor for vascular dementia. The problem is that when you exclude individuals with vascular dementia, the effect of diabetes on Alzheimer's disease depends on where you draw the line between the two. Also, there are some who would argue that Alzheimer's disease has a vascular component or that it is on a continuum with vascular dementias.

There is clearly something going on there, but I get the impression the field is still trying to tease apart the effects purely do to insulin resistance and the secondary effects of poor vascular health.

Thanks for taking this on by the way, Evil Monkey.

There is a guy in my lab who works on the association of cholesterol and Abeta production, so I have heard of a lot of this stuff, but it is definitely not my area.

Thanks Jake
I didn't even think of vascular dementia but it makes since that diabetes would be a problem vascularly. I think it would be good to review the Nun studies because all the literature generally says use your brain or lose it but they rarely mention the vascular causes of dementia. So I think it would be good to see all the data on the health of the nuns as far as weight and blood pressure to see if they had overall good health versus its just because they were more intelectual.