Alzheimer's and RAGE

Something I wrote in an email a while ago . . .

Advanced glycation endproducts (AGEs) are the endpoints of some complicated chemistry that occurs when simple sugars (glucose, fructose, etc.) react with proteins (and apparently fats too). They’re toxic for a variety of reasons, and trigger an inflammatory response via the receptor for advanced glycation endproducts, or RAGE.

It turns out that RAGE binds to a whole bunch of things, and amongst them is the amyloid beta peptide, which is implicated in the development of Alzheimer’s. Amyloid beta is apparently produced via neural activity. I can’t figure out if it has a function or is just a by-product. I suspect it has some function, because the body has a mechanism for achieving a balance in the central nervous system (CNS). One kind of receptor (LRP) causes active transport out of the CNS to the blood, while RAGE triggers transport from the blood to the CNS across the blood-brain barrier. More RAGEs means you’ll have more amyloid beta in your brain. I couldn’t verify this, but I would guess that insulin drives the formation of RAGE. It makes sense, as your body would be preparing for glycation damage (more AGEs) from increased blood sugar, whether the source was food or glucose released due to stress. And indeed, diabetics have higher concentrations of RAGE (as do the blood vessels in the brains of Alzheimer’s victims).

We learned today that stress actually increases amyloid beta production in the brain, via the action of corticotrophin releasing factor, or CRF. I got in contact with one of the authors of that study and he was nice enough to send me a reprint of the paper. It’s a pretty solid piece of research. Amongst other things, they showed that the more you stress mice, the more amyloid beta is produced. They could introduce CRF directly into the brain, and observe increased amyloid beta production. They could block the action of CRF, stress the mice, and see that less amyloid beta was produced. And finally they could directly block neural activity, and either stress the mice or introduce CRF, and again would see reduced amyloid beta. So it was a pretty solid case, albeit in mice. It would be surprising if humans turned out to be much different, though it’s certainly possible. CRF is released as part of the stress response. It is also released as a result of insulin-induced hypoglycemia, i.e. insulin goes up, blood sugar crashes, CRF pumps out.

One last piece of the puzzle: by itself, amyloid beta is soluble, and shouldn’t form solid plaques (or at least do so slowly). But test-tube experiments show that formation of solid “fibrillar aggregates” of amyloid beta are accelerated if you provide seeds of altered amyloid beta. And what’s one form of the alteration? Glycation damage from sugar.

So, less than surprisingly my hypothesis is that the route to Alzheimer’s mirrors that of heart disease. A high-carbohydrate diet leads to the following effects:

1. Increase in density of receptors for advanced glycation endproducts, which leads to increased amyloid beta concentrations in the brain.
2. Release of CRF, which increases production of amyloid beta in the brain.
3. Damage to amyloid beta, which increases the formation rate of solid aggregates, which may be contributory toward the formation of the plaques associated with Alzheimer’s.

And of course, there’s the usual feedback between stress and diet: psychosocial stress makes you want to eat more carbohydrates, which makes you more stressed, etc.