Alzheimer’s Disease (AD) is the most common neurodegenerative disorder diagnosed today. For a long time it was unclear as to the cause of AD, and there is still much to learn, but scientist have discovered a key player in the onset of this disease: insulin.
Normally, insulin is associated with Diabetes. Type II Diabetes involves an inability of the pancreas to develop insulin properly, and Type I is a resistance to insulin. Both result in blood sugar (glucose) not being able to be taken up by cells, resulting in high blood sugar. In turns out, there may be something similar going on in Alzheimer’s Disease.
Cells throughout your body have insulin receptors, including your brain. The insulin receptors in your brain are the beginning to two major pathways: the PI3K pathway, and the MAPK pathway. Normally, both of these pathways get activated when insulin binds to its receptors. Both pathways balance each other out and everything works well. However, when you develop insulin resistance (similar to in Diabetes) the PI3K pathway no longer gets activated while the MAPK pathway still does. The MAPK pathway is mostly involved in vasoconstriction, whereas the PI3K pathway is involved in neuroprotection, neuron plasticity, vasodilation, and the inhibition of an enzyme called GSK3-beta among other actions as well.
As you can probably guess, the inactivation of this PI3K pathway is not a good thing. Neurons begin to die because the neuroprotective effect of PI3K is no longer occurring. Also, when GSK3-beta is not inhibited, it tends to run rampant and hyperphosphorylate things like the protein TAU. The distinguishing characteristic of AD is amyloid beta plaques and neurofibrillary tangles that develop in the brain. The hyperphosphorylation of TAU is what leads to these neurofibrillary tangles. The inhibition of the PI3K pathway is also associated with the amyloid beta plaques as well.
It has been found that treating AD patients with insulin can alleviate some of the symptoms. This is most likely because the increase in insulin is activating a few more of the receptors and the PI3K pathways. However, this treatment option has also been shown to be negative in some cases. This may be due to the person not actually having insulin resistance. If you start taking a lot of insulin when your receptors function normally, you can overwhelm them and potentially develop resistance, doing more harm than good. I think it is necessary to develop a method of determining if someone truly has insulin resistance in order to treat them properly. More research also needs to go into figuring out ways to reactivate this PI3K pathway in a safe manner. AD still does not have a cure, but scientists are well on their way.
Type 3 Diabetes? The Link Between Diabetes and Alzheimer's Disease
This is Alzheimer’s disease in a nutshell. The neuroprotective phosphatidyinositol-3 kinase/Akt pathway gets cut off and as a result the neurodestructive p38 MAPK pathway is activated instead.
Activation of the phosphatidylinistol 3-kinase/Akt pathway leads to increased blood flow in the brain, the maintenance of antioxidant levels in the brain, and the regeneration of neurons in the brain. P38 MAPK via peroxynitrite leads to oxidative and nitration damage of critical receptors, enzymes and transport systems in the brain. Specifically peroxynitrite inhibit the synthesis and release of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, deplete antioxidants in the brain, restrict blood flow in the brain, reduce the transport of glucose in the brain which can result in wandering, apathy, and delusions, may severely overactivate NMDA receptors resulting in hallucinations, led to the hyperphosporylation and nitration of tau proteins which hinders neurotransmissions and the transport of nutrients in the brain, and cause the death of neurons.
Receptor tyrosine kinases and g protein-coupled protein receptors can activate either the phosphatidylinositol-3 kinase/Akt pathway or the p38 MAPK pathway. Overactivation of either receptor type can lead to Alzheimer’s disease. The factors that can cause this overactivation are many. They include but are not limited to hyperinsulinemia, high glucose levels, mercury, various pesticides and herbicides, certain industrial solvents, a number of air pollutants, psychological or physical stress, heavy drinking, heavy smoking, presenilin 2 gene mutations, the Apoe4 gene, amyloid precursor protein mutations, and certain chronic viral, bacterial, and perhaps fungal infections. Alzheimer’s disease is so widespread because the factors that can activate the receptors that trigger the disease are so numerous.
Presenilin 1 gene mutations which are responsible for many cases of early onset Alzheimer’s disease and peroxynitrite-mediated nitration cut of the neuroprotective phosphatidyinositol/Akt pathway. The problem, though, is that they do not cut off the neurodestructive p38 MAPK pathway which continues to be activated through NMDA receptors.
One last factor in Alzheimer’s disease is high levels of myo-inositol. High glucose levels (due to a high carbohydrate or high sugar diet), high blood pressure due to high sodium levels, and Down syndrome all increase myo-inositol levels in the brain. More glucose (and more insulin) ends up in the brain due to type 2 diabetes (which itself may be caused by the inhibition of the phosphatidyinositol-3 kinase) and this is why type 2 diabetes increases the risk for Alzheimer’s disease
Myo-inositol is converted into phosphatidyinositol 4,5 triphosphate which is the substrate for the phosphatidylinositol-3 kinase, but is also the substrate for phospholipase C. Phospholipase C leads to the activation of protein kinase C, NMDA receptors, p38 MAPK, and peroxynitrite (less importantly it leads to amyloid oligomers and hyperphosphorylated tau via intracellular calcium release).
It does not matter how much amyloid or how many tau tangles, a person has in their brain, as long as peroxynitrites are being scavenged a person does not develop Alzheimer’s disease. Once peroxynitrites stop being scavenged, then one has to turn to external antioxidants to treat the disease. This includes eugenol in various essential oils via aromatherapy (Jimbo, et al. 2009) and ferulic acid and syringic acid in panax ginseng (Heo, et al. 2011 and 2012).
High glucose levels and high insulin levels (which ultimately lead to insulin resistance in the brain as well with still yet undetermined consequences as it is not clear what role insulin plays in glucose levels in the brain) are two of many causes of Alzheimer’s disease. But the compounds and pathways that lead to the disease are usually the same: high levels of myo-inositol, overactivation of either or both receptor tyrosine kinases or g protein-coupled receptors, and inactivation of the neuroprotective phosphatidylinositol 3-kinase/Akt pathway. All result in the activation of the p 38 MAPK kinase and the formation of peroxynitrite. Inhibiting peroxynitrite formation, scavenging peroxynitrite, and reversing part of their damage via selective antioxidants is the key to preventing and partially reversing Alzheimer’s disease.