Living in a society where overindulgence of food is commonplace and obesity rates are rampant, we are well aware that too much sugar and fat in our diets is bad for our health, as it can lead to diabetes and heart problems. But it’s not just our hearts that we should be concerned about: this sugar overload may very well be breaking down our brains too. Recent research has discovered that insulin resistance seen in Type 2 diabetes is involved in the development and pathology of Alzheimer’s disease; some scientists are even referring to Alzheimer’s as Type 3 diabetes.
Many people know someone with diabetes or have at least heard about it from a popular infomercial and this man’s pronunciation of the disease:
My first exposure to diabetes was seeing my uncle, who has Type I diabetes, inject insulin into his leg and asking my mom why he got to eat M&M’s for dinner and I didn’t. I didn’t fully understand how sugar in the body worked or why he needed to give himself shots several times a day. Insulin is a hormone created in the body that helps regulate glucose levels in your blood. Too much glucose in your blood is toxic. However, in the case of diabetes, insulin is either not being produced in the body at all or in insufficient amounts (Type 1) or in the case of Type 2 diabetes, the body becomes resistant to insulin, meaning that cells fail to respond to the normal actions of insulin, so blood sugar is no longer being regulated. Type I is often referred to as childhood diabetes, the type that is not related to food or lifestyle choices.Type II is the type of diabetes whose onset results from an unhealthy lifestyle, correlated with obesity. With increased levels of sugar in your diet, the body will initially produce more insulin to help regulate blood glucose levels, but eventually it cannot make enough insulin to keep up with the demand, and the body no longer responds to insulin.
So how does insulin relate to Alzheimer’s? Alzheimer’s disease is a progressive neurodegenerative disease characterized by neurofibrillary tangles and beta-amyloid plaques. Insulin and insulin-like hormones activate the PI3-kinase/Akt pathway. This pathway is involved in transmission of pathophysiological responses from amyloid-beta to tau, two important proteins. When insulin responses are desensitized in the brain, it leads to an increased activation of this pathway. When this pathway is over-activated, it leads to changes in amyloid-beta modulation and missorting and hyperphosphorylation of tau protein. Amyloid-beta is a protein fragment produced normally in the body. In Alzheimer’s, these fragments are not broken down like they should, and they clump together, forming plaques in the brain, which kill neurons. This means decreased neuronal communication in parts of the brain responsible for memory, resulting in worsening memory recall as the brain degenerates.
Tau missorting creates another problem seen in AD brains: neurofibrillary tangles. Let’s think of tau in terms of a college student doing laundry, and assume that the student normally folds and sorts their clothes and puts them in organized drawers (and for the sake of their mother’s sanity). Normally, clothes are always folded neatly, sorted by article of clothing, and put in their respective drawers. However, with increased stress with too many things to do, the student is overactivated, working too hard, and becomes fatigued. This affects their laundry routine. Clothes are missorted and no longer folded properly, ending up in piles on the floor instead of where they are supposed to be. Eventually, the piles become so severe, the tangles of clothes obstruct pathways needed to get to their bed, and the student can no longer reach it. Like the piles of clothes, tau gets misfolded and missorted and accumulates, creating tangles eventually blocking pathways and neuronal communication, causing neurons to die in areas of the brain involved in memory, like the hippocampus, this is how the progressive memory loss occurs in Alzheimer’s disease.
Without insulin being regulated and used properly, the PI3-kinase/Akt pathway is overactivated, causing malfunctions in protein breakdown and sorting, leading to plaques and tangles that destroy neurons in brain areas involved in memory, key characteristics of Alzheimer’s disease. With so many factors contributing to the onset of AD, it is difficult to pinpoint an area that is effective for treatment. However, with the knowledge of the relationship between insulin resistance and Alzheimer’s disease, we do have a possibility of effective prevention: eating healthy and exercising. We’ve been told time and time again that this is important, but this is further proof that we need to take care of our bodies to not only keep us in good physical shape but also good mental shape as we age. If not for you, do it for the ones you love. Because I’d rather be able to relive memories with my loved ones than to have my loved ones be witness to me losing the memories we once shared and eventually, forgetting who my loved ones are altogether.
Image retrieved from: http://www.quickmeme.com/meme/3rr0nc
Is your sweet tooth breaking down your brain? Insulin’s role in Alzheimer’s Pathology
Insulin resistance and Alzheimer’s disease are basically two sides to the same coin. In the case of type 2 diabetes, the nitration of the insulin receptor substrate prevents the uptake of glucose. In Alzheimer’s disease, the nitration of the phosphatidylinositol 3-kinase leads to the formation of amyloid, neurofibrillary tangles, the decrease in blood flow in the brain, an end to the regeneration of neurons in the brain, and to the death of brain cells.
Peroxynitrites mediate much of the nitration that occurs in the brains of people with Alzheimer’s disease and results in the death of neurons
http://www.nature.com/cdd/journal/v13/n9/full/4401831a.html
The article that was assigned to you and to your classmates is throwing everyone off. The two pathways that lead to Alzheimer’s disease are over-activation of tyrosine receptor kinases and g protein-coupled receptors (or direct g protein activation). These receptors activate the phosphatidylinositol 3-kinase and Akt but they also activate p38 MAPK. In the rest of the body this dual activation continues and can lead to cancer but in the brain only p38 MAPK continues to be activated and this leads to the death of brain cells. This is why most people who have cancer do not get Alzheimer’s disease and why most people with Alzheimer’s disease don’t get cancer.
Neurofibrillary tangles and amyloid oligomers may contribute to the death of neurons but they are not the primary cause. The primary cause is peroxynitrite. Thus, all the efforts to deal with tau tangles and amyloid have failed, while all the trials using specific peroxynitrite scavengers have succeeded. For instance trials using aromatherapy (Jimbo), lemon balm–Melissa officinalis (Akhondadeh), Korean red ginseng (Heo), and heat processed ginseng (Heo). I will end with the wisest quote regarding the treatment of Alzheimer’s disease.
[Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation or on antioxidants which scavenger oxygen derived free radicals. Most of these items have proved to be worthless in the
treatment of Alzheimer’s disease. Similarly most drugs used to treat Alzheimer’s disease do little to slow the deterioration, but instead offer a mild temporary symptom relief. However, evidence has been accumulating that the primary driver of Alzheimer’s disease is a nitrogen derived free radical called peroxynitrites which may mediate both amyloid and tau accumulation as well as their toxicity. Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer’s disease being repeatedly demonstrated. IMHO, the only thing which may be preventing the abolition of Alzheimer’s disease is the mental inertia of scientists as well as the bureaucrats who fund them. Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones. Common sense is anything but…]
Thanks for your comments. It is interesting to see the effects of scavenging peroxynitrite on AD….and very promising! We were looking at the complexity of the signaling that is disrupted in AD and while we did not talk about the MAPK pathway, realize that singling in one one pathway does not tell the whole story. (Although it sounds like peroxynitrite can!) In looking at the snowball effect of activation of the akt/PI3K/mTOR pathway causing AB formation leading to more activation of the pathway, the initiation of the entire process might simply be aging. Aging’ role in neurodegenerative disease is interesting. Thanks again for the comments; we will look at peroxynitrite for next year’s article.
Thank you very much for your reply. I come here each Fall to read the very informative student articles. I remember the articles on p38 MAPK from a couple of years ago.
I have seen very positive results using peroxynitrite scavengers to treat Alzheimer’s disease from my mother, to friends with the disease, to testimonials, to their use in memory care facilities, to small-scale clinical trials. I would be very pleased to read your students’ comments next year.
I am working on a short bibliography of peroxynitrites in Alzheimer’s disease, factors that increase or decrease peroxynitrite formation, and a diagram showing the pathways to their formation. I will try to remember to send you a copy of each in a few weeks.