To wrap up this past weekend, I watched The Notebook while folding my laundry. It was an applicable movie to the Neurochemistry class topic of the past week, Alzheimer’s Disease (AD). Though fiction, the movie brings up difficult topics that come along with aging. What if your loved ones develop AD and can’t remember you? What if you develop the disease and can’t remember your own life? And how does one develop AD anyway?
Alzheimer’s disease is a complex disease in which no cure is currently available and a lot of information about the causation of the disease is missing. Though AD can be genetic in a rare early-onset form and genetics such as having the ApoE4 allele can be a risk factor, the main risk factor for the disease is merely aging. Since we all have to age, this begs the question of whether or not we can take steps to prevent getting AD. The author of the article we read in class seems to think so.
In the article, one major biochemical pathway in the brain is discussed in detail as it relates to Alzheimer’s disease. This is the PI3K/Akt/mTOR pathway. In this pathway, insulin or a growth factor binds to a receptor (called a tyrosine kinase receptor) that initiates responses from proteins such as IRS, PI3K, Akt, and mTOR. These proteins work together to create an overall response to induce more cell growth and protein translation of proteins such as tau and APP (amyloid precursor protein). Some of these proteins also inactivate other proteins such as FOXO and GSK3β which are responsible for protection of neurons and stress responses in the cells.
Over-activation of the pathway mentioned above leads to the build-up of tau proteins and APP which can later lead to the dreaded neurofibrillary tangles and amyloid-beta plaques associated with Alzheimer’s disease. Not activating the pathway at all was shown to be fatal in mice. Thus, the article highlights that a balance of activation and inactivation of this protein pathway is needed in the body. But with aging comes the over-activation of the pathway in the brain neurons and thus the onset of AD.
Since the pathway is activated by insulin, a better regulation of insulin in the body may decrease one’s risk of over-activating the pathway and building up more tangles and plaques that cause signaling problems in the brain and are associated with AD. Insulin release in the body is triggered by presence of glucose which comes from the breakdown of food. The author of the article proposed that less consumption of calories and more exercise might lead to a decreased risk of AD due to less activation of the pathway described.
Though research is continually being done, AD is not a fully categorized and understood disease. The current state of knowledge about the disease may not provide much comfort to baby-boomers soon to be at the age in which AD progresses, but hopefully sooner rather than later, researchers find a cure or better treatments or at least more concrete causes for the disease.
Referenced Article:
http://www.ncbi.nlm.nih.gov/pubmed/23470275
Picture from:
http://www.alz.org/braintour/plaques_tangles.asp
Forget-Me-Not: What Really Happens in the Brain in Alzheimer’s Disease?
There are four potential triggers for Alzheimer’s disease: high levels of myo-inositol, overactivation of tyrosine receptor kinases, overactivation of g protein coupled receptors (or direct activation of g proteins), and inhibition of the phosphatidylinositol 3-kinase/Akt pathway (by presenilin gene mutations and bisphosphonate drugs such as Fosamax, for example).
The end result of the overactivation of tyrosine receptor kinases and g proteins is the production of peroxynitrites. In the brain, peroxynitrites nitrate and cut off the phosphatidylinositol 3-kinase/Akt pathway. The result is decreased blood flow in the brain, the decreased regeneration of neurons in the hippocampus, decreased internal antioxidants in the brain, and the death of brain cells.
High glucose levels, hyperinsulinemia, high sodium levels, high fructose corn syrup, carbohdydrates, environmental toxins such as mercury, aluminum fluoride, bisphenols, various air pollutants, and various pesticides and herbicides, various chronic and bacterial infections, smoking and stress can all lead to high levels of peroxynitrites and increase the risk of Alzheimer’s disease. Various peroxynitrite scavengers such as eugenol in various essential oils (such as rosemary, clove, and bay laurel), eugenol and ferulic acid in lemon balm (Melissa officinalis) extract, and ferulic acid, vanillic acid, syringic acid, p-coumaric acid, and maltol in panax ginseng have partially reversed Alzheimer’s disease in human clinical trials (see studies by Jimbo on aromatherapy, Akhondzadeh on lemon balm, and Heo on ginseng). Reducing the activation of tyrosine receptor kinases with polyphenols (which are also peroxynitrite scavengers) helps protect against Alzheimer’s disease while the most powerful polyphenols such as the compounds listed above help treat Alzheimer’s disease.
I know see where the confusion regarding the role of the phosphatidylinositol 3-kinase/Akt pathway is coming from. The overactivation of tyrosine receptor kinases and g protein-coupled receptors do indeed lead to the early activation this pathway, but it also leads to the overproduction of p38 MAPK and to the subsequent formation of peroxynitrites.
In the brain, peroxynitrites nitrate the phosphatidylinositol 3-kinase and thus inhibits Akt. This results in a reduced blood flow in the brain, a decrease in the brain’s antioxidant systems, the hyperphosphorylation of tau proteins (which with along with their subsequent nitration interferes with neurotransmissions). Peroxynitrites also lead to the death of brain cells.
Cell Death Differ. 2006 Sep;13(9):1506-14. Epub 2006 Jan 20.
Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells.
Shacka JJ1, Sahawneh MA, Gonzalez JD, Ye YZ, D’Alessandro TL, Estévez AG.
Author information
Abstract
The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.
The problems in the brains of people with Alzheimer’s disease begins before the formation of tangles and the deposition of amyloid. Peroxynitrites increase the beta secretase and the subsequent formation of the c-terminal fragment of the amyloid precursor protein. Early on, this leads to the formation of more peroxynitrites and to the death of neurons.
Alzheimer’s Disease Without Amyloid Plaques
Posted on 05. Oct, 2011 by Admin in medicine, biology
Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death. The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.
J Neurochem. 2001 Jul;78(1):109-20.
C-terminal fragment of amyloid precursor protein induces astrocytosis.
Bach JH1, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS.
Author information
Abstract
One of the pathophysiological features of Alzheimer’s disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites. In the present study, we investigated the possible role of the C-terminal fragment of amyloid precursor protein (CT-APP), which is another constituent of amyloid senile plaque and an abnormal product of APP metabolism, as an inducer of astrocytosis. We report that 100 nM recombinant C-terminal 105 amino acid fragment (CT105) of APP induced astrocytosis morphologically and immunologically. CT105 exposure resulted in activation of mitogen-activated protein kinase (MAPK) pathways as well as transcription factor NF-kappaB. Pretreatment with PD098059 and/or SB203580 decreased nitric oxide (NO) production and nuclear factor-kappa B (NF-kappaB) activation. But inhibitors of NF-kappaB activation did not affect MAPKs activation whereas they abolished NO production and attenuated astrocytosis. Furthermore, conditioned media derived from CT105-treated astrocytes enhanced neurotoxicity and pretreatment with NO and peroxynitrite scavengers attenuated its toxicity. These suggest that CT-APP may participate in Alzheimer’s pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.
The key to treating Alzheimer’s disease is to scavenge peroxynitrites and to reverse their damage in regards to oxidation and nitration. While efforts to remove amyloid and tau tangles have continued to fail, small-scale clinical trials using methoxyphenols which are among the best peroxynitrite scavengers have all succeeded. This includes eugenol in rosemary essential oil via aromatherapy (Jimbo, 2009), eugenol and ferulic acid in lemon balm–Melissa officinalis extract (Akhondzadeh, 2004), and ferulic acid and syringic acid in red Korean and heat-processed ginseng (Heo 2011 and 2012).
The following quote sums up the cause and 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…]
Sorry, I should have said I now see where the source of the confusion comes from.
If the over-activation of the phosphatidylinositol 3-kinase/Akt pathway is the problem in Alzheimer’s disease why might giving insulin and insulin like growth factor which stimulates this kinase help?
There are four major tyrosine receptor kinases in the brain: insulin, insulin like growth factor, platelet derived growth factor, and epidermal growth factor receptors. Any when over-activated can not only initially over-activate the phosphatidylinositol 3-kinase but also protein kinase C leading to the activation of p38 MAPK and the formation of peroxynitrites. The last two receptors (platelet derived growth factor and the epidermal growth factor) appear to be the strongest culprits in the formation of peroxynitrites because they activate protein kinase C more than they activate the phosphatidylinositol-3 kinase; whereas the reverse appears to be the case with insulin and insulin like growth factor receptors. So some insulin and insulin like growth factor may help initially, but too much will harm the brain.
Moderate exercise stimulates the phosphatidylinositol-3 kinase/Akt pathway. High glucose levels (from sugar and carbohydrates), high sodium levels, high fructose corn syrup, presenilin gene mutations, the Apoe4 gene, biphosponate osteoporosis drugs such as Fosamax, benzodiazepines for anxiety, various pesticides and herbicides, bisphenols, various air pollutants, mercury, aluminum fluoride, sodium fluoride, and stress will cut it off. These are among the risk factors for Alzheimer’s disease.