This week, I would like to talk to you about Alzheimer’s disease, a serious disease that has been brought up on this blog before just a couple weeks ago. When we talked about it before, we brought up the topic of diabetes and how the malfunctions of insulin in a diabetic patient could lead to Alzheimer’s disease. This week I will talk about another pathway scientists believe may be a factor in the development of Alzheimer’s disease.
This week, we focus in on the MAPK pathway. This pathway is responsible for several operations within our extremely complex bodies, but we will be concerned with its effects on cell proliferation, growth, and death. The pathway works through a series of activating different proteins within the cell and when each protein is activated, it can go off onto its own path and either promote cell growth or cell death.
As you know already, Alzheimer’s is signified by a buildup of Aβ plaques and neurofibrillary tangles within the brain. But what is believed to be the cause of these buildups? Well, scientists believe that activation of these MAPK pathways through oxidative stress (a risk factor for Alzheimer’s) eventually lead to a certain protein or enzyme which promotes neuron destruction which will lead to Alzheimer’s. As you can imagine, the actual process is a lot more complex, but we’ll keep it simple here.
When we compare the two paths for Alzheimer’s we have covered thus far, we must ask ourselves, “Is one of these a better option than the others when looking into curing this disease? And if so, where would our money be better spent?” Personally, I think the MAPK pathway is a more important area of research than the diabetes. To me, the rate of diabetes in the country can be significantly lowered just by changing your lifestyle, which really isn’t too hard. It just involves eating a little healthier and going outside a little more. If everyone in the nation did this alone, I feel it would cut our diabetes in half and thus lower their risk for developing Alzheimer’s disease, therefore not worth our time to research. The MAPK pathway, however, is not something we can change as easily. The oxidative stress comes from our lifestyle and how stressful it is, but it is not as easy to change that as it is in the diabetes case. The MAPK pathway also has implications in many other diseases such as Parkinson’s disease, ALS, or even cancer, so research in that area could also prove to be crucial in several other diseases. The only problem with working on the MAPK pathways brings up is the fact that they DO control so much in our body, it is not a single pathway we can just stop. It is a nasty maze that hurts your eyes looking at the entire pathway (see image), but perhaps more research in the area would help overcome that obstacle.
As you can see, the MAPK pathway proves to be crucial in the development of Alzheimer’s disease and personally, I think money should be invested into researching this area more in hopes of a brighter future.
A Hopeful Future for Alzheimer's Patients?
The key to preventing or at least delaying the onset of Alzheimer’s disease is to work upstream from MAPK. In particular, the inhibition of phospholipase C will inhibit the activation of MAPK, the formation of amyloid plaques, the hyperphosphorylation of tau proteins, and the formation of peroxynitrites–the prinicipal oxidant in Alzheimer’s disease. Phospholipase C gamma can be inhibited by polyphenols in various fruits, vegetables, spices, teas, and essential oils. The activity of phospholipase C gamma and beta can likely be dampened by polyunsatured fats such as fish oil.
The key to treating Alzheimer’s disease is found in compounds that scavenge peroxynitrites and repair part of their oxidative damage to key transport systems,enzymes, and receptors in the brain, including those involved in short-term memory. The best of these scavengers are methoxyphenols because by donating two electrons and two hydrogren atoms they convert peroxynitrites into water and a nitrite anion (ONOO- + 2H+ + 2e-= H20+ NO2-). Moreover, because they are excellent hydrogen donors, methoxyphenols reverse part of the oxidative damage caused by peroxynitrites.
Two clinical trials using methoxyphenols (eugenol in rosemary essential oil and ferulic acid, coumaric acid, syringic acid, and vanillic acid in heat-processed ginseng) have led to significant improvements in cognitive function in patients with Alzheimer’s disesae. See, Jimbo, et al. Effect of aromatherapy on patients with Alzheimer’s disease (2009) and Heo, et al. Heat-processed ginseng enhances cognitive function in patients with moderately severe Alzheimer’s disease (2012).
Find the trigger for oxidative stress (phospholipase C) and you can prevent or at least delay the onset of Alzheimer’s disease; find the oxidant causing most of the damage (peroxynitrites) and you can effectively treat (not cure) Alzheimer’s disease.
Although I somewhat agree with what you are saying, and the research does seem fruitful, I don’t see inhibiting PLC to be the treatment for Alzheimer’s. PLC has a great effect on the cell in creating PIP2 and DAG from IP3 both of which provide very useful effects on the cell, such as PIP2 activating PKC, which plays a key role in several signal transduction cascades outside of learning and memory.
Under normal circumstances, you are correct, but the problem in Alzheimer’s disease is the overactivation of this pathway. High levels of myo-inositol (due to high levels of glucose–diabetic or pre-diabetic, high blood pressure caused by high sodium levels, or Down syndrome), the inhibition of the phosphatidylinositol 3 kinase (by presenilin gene mutations, the APOE4 gene,or bisphsophonate osteoporosis drugs such as Fosamax), and high phospholipase C beta and gamma activity (due to stress, mercury, aluminium fluoride, chronic bacterial and viral infections, high glucose levels, angiotensin II to name a few) leads to the increased production of inositol 1,4,5 triphosphate which as you note activates Protein kinase C and leads to intracellular calcium release. Protein kinase C activity triggers the production of the chief oxidant in Alzheimer’s disease–peroxynitrites, and the combination of protein kinase C and intracellular calcium release leads to the production of amyloid plaques. See Buxbaum. et al. Calcium regulates processing of the amyloid protein precursor in a protein kinase C-independent manner; and the KEGG pathway for Alzheimer’s disease. Due to nitration and oxidation phospholipase C activity declines as Alzheimer’s disease progresses. However, amyloid plaques by entombing zinc increase homocysteine which via protein kinase C ensures the continuation of high levels of peroxynitrites. Peroxynitrites in turn increase the aggregation of plaques through nitration. A Mediterranean and an Indian diet (curcumin and other spices) may help to protect against Alzheimer’s disease not only by inhibiting phospholipase C gamma activity but by inhibiting the production of superoxide anions and inducible nitric oxide via Protein kinase C (superoxides and inducible nitric oxides combine to form peroxynitrites). If you are able to inhibit the formation of peroxynitrites, you are able to prevent or delay the onset of Alzheimer’s disease. If you can scavenge and repair part of the damage done by peroxynitrites you can effectively treat Alzheimer’s disease.
Further evidence that at least initially the overactivation of phospholipase C (in this case phospholipase C gamma) plays a role in brain disorders, including Alzheimer’s disease:
Adv Biol Regul. 2012 Sep 18. pii: S2212-4926(12)00092-9. doi: 10.1016/j.jbior.2012.09.008. [Epub ahead of print]
Phospholipase C-γ1 involved in brain disorders.
Jang HJ, Yang YR, Kim JK, Choi JH, Seo YK, Lee YH, Lee JE, Ryu SH, Suh PG.
SourceSchool of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea; Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Abstract
Phosphoinositide-specific phospholipase C-γ1 (PLC-γ1) is an important signaling regulator involved in various cellular processes. In brain, PLC-γ1 is highly expressed and participates in neuronal cell functions mediated by neurotrophins. Consistent with essential roles of PLC-γ1, it is involved in development of brain and synaptic transmission. Significantly, abnormal expression and activation of PLC-γ1 appears in various brain disorders such as epilepsy, depression, Huntington’s disease and Alzheimer’s disease. Thus, PLC-γ1 has been implicated in brain functions as well as related brain disorders. In this review, we discuss the roles of PLC-γ1 in neuronal functions and its pathological relevance to diverse brain diseases.
Thanks for your work and all the other students who work on this project for very clearly explaining complex biological processes.
I am an environmental historian not a scientist, but I spent many years studying this disease to help my mother. With the help of aromatherapy she was able to live a longer and better life.