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.
ALS – The Science Behind the Disease
Amy
otrophic Lateral Sclerosis (ALS), or Lou Gehrig’s Disease, is a fatal neurodegenerative disorder that results in the withering away of muscles due to the malfunction of motor neurons that travel from the spinal cord to the various skeletal muscles in the body. The lateral part of the spinal cord containing these motor neurons develops “sclerosis” where it hardens due to certain glial cells conglomerating together and essentially forming a scar in the spinal cord. This disrupts the signal that the motor neurons bring to the muscles, and eventually results in the muscles not being able to contract and “atrophying,” or withering away.
There has been a recent surge in the recognition of ALS with the “Ice Bucket Challege” that I’m sure most of us either heard about or participated in. ALS is a very debilitating disease that results in requiring a wheelchair to get around and eventual death. At this point there is no cure, and I’m not sure that a true “cure” will ever be developed. However, the recent advancements in scientific research are beginning to show us the possible root cause of this disease and possible treatments to help prevent and delay the development and progression of this debilitating disease.
There are receptors on neurons throughout your body called NMDA receptors. They are usually found with another receptor called AMPA. These are both responsive to a neurotransmitter called glutamate. In ALS, and other nuerodegenerative diseases, there is too much glutamate causing these receptors to activate, letting a lot of calcium into your cells. This calcium puts stress on the organelles inside the cell, especially the mitochondria and the endoplasmic reticulum (ER). This stress signals cell death in many cells. It also causes the ER of cells still alive to not fold proteins correctly; a specific misfolded protein called SOD1 is thought to play a major role in ALS because it leads to the accumulation of Reactive Oxygen Species (ROS) that can cause a lot of damage within cells. Glial cells help out neurons, and in this case they surround the damaged motor neurons to help prevent further damage. This is what results in the hardend scars found in ALS. Scientists are still uncertain to why the motor neurons in the spinal cord are the only cells that are affected in ALS. It may have to do with the type and amount of NMDA receptors found in motor neurons, but this is still unclear.
At any rate, this further understanding had lead to new developments within the treatment of ALS. NMDA receptor blockers may potentially be able to alleviate some of the effects of ALS. This is tricky however, because these receptors are found elsewhere in the body and their normal healthy function is necessary. Also, antioxidants, even like those found in grapes and blueberries, could also help stop some of the damage caused by the ROS. The best bet is a combination of NMDA antagonists, antioxidants, and cell stress reduction through a healthy lifestyle. More research is necessary to understand the full mechanism of this disease, which is essential in creating the most efficient treatment plan. Scientists are on their way to cracking the code of ALS, but they haven’t quite found it yet.
The Surprising Relationship between Insulin and Alzheimer's
There exists a link between type II diabetes and Alzheimer’s. People who have type II diabetes are at a significantly higher probability of developing Alzheimer’s. This is due to numerous reasons, one of which being a resistance to insulin means that different pathways in the brain are over activated, which can lead to cell death, or aren’t activated (because the cell requires more to activate) which will also eventually lead to cell death. Neurons dying in the brain are irreplaceable and are major contributors to Alzheimer’s. While treatment exists, like an intranasal insulin spray (Detemir) has been shown to improve memory. While memory does improve, it is merely treating a symptom of the disease and not the disease itself.
Ultimately the connection between diabetes and Alzheimer’s surprised me, it does make sense. Looking at many people who have developed type II diabetes in my life and looking at their cognitive faculties. While many of these people are also much older than I (in their sixties and seventies) so I have to take this information with a grain of salt. As a species as we age our cognitive functions decrease simply due to wear and tear. This raises the question for me: are they actually showing signs of Alzheimer’s or is it an effect of aging?
While the end result may be the same actually having a name for what is happening to them somehow makes it more… bearable. If it’s aging, or if it’s Alzheimer’s knowing which one it is, for me, would be a big deal, and not knowing if the reason I’m losing my mental faculties is because of my age or a neurodegenerative disease would bother me to my dying day. While I will probably develop Alzheimer’s or a similar neurodegenerative disease later in my life, I hope that by then some sort of pharmaceutical or therapy will be able to restore cognitive functions… Even if it’s just temporary.
Endocannabinoids and their Classification
Endocannabinoids are a group of chemicals that exist within the human brain and various drugs like marijuana (hence the endo meaning within and cannabinoids… cannabis). They are the chemicals that are able bind to our CB1 and CB2 receptors to give us the psychotropic effects of smoking marijuana. In addition to the standard psychotropic effects, there are also innumerous beneficial effects ranging from decreasing nausea to helping cancer patients eat to remain healthy. Marijuana has over 400 chemical compounds that work in tandem to cause the effects normally associated with smoking or consuming marijuana. While scientists have tried to isolate the compounds that have been shown to help with nausea/pain control (THC for example), when taken without the other 400 chemicals their effects appear mitigated, and some of the negative side effects associated with marijuana become more pronounced. Leading some to believe that nature has perfected something that scientists will never quite replicate.
Regardless of one’s opinion on marijuana, we should agree that it shouldn’t have been classified as a schedule I drug. Schedule I drugs are drugs that have a high potential for abuse and have exactly zero medical benefits associated with them. With states legalizing medical and recreational usage of marijuana more research is starting to show it has beneficial effects when used correctly. This means that it should not be a schedule I drug, and at most a schedule II drug (a drug that has a high potential for abuse but has medically relevant uses). Whatever your opinion on recreational use of the drug there is no doubt that it should be reclassified as a lower schedule drug.
It is my opinion that since the endocannabinoid system within the brain is vaguely understood the use of recreational marijuana should be postponed until more is understood. Currently the only two known receptors for endocannabinoids are CB1 and CB2, however researchers believe that there might be as many as four receptors (if not more). While not knowing how many receptors might be found within the brain is semi common, what is concerning is how readily people are willing to consume a drug that scientists don’t even understand some of the effects of. While predicating recreational use of a drug based off of complete understanding of the compound is more than a little outrageous, not to mention impossible (since scientists will rarely, if ever, claim to know everything), waiting until medically useful background is established is important. Understanding the long term impact of smoking marijuana that is quantified in cold hard statistics is the biggest factor right now in preventing me from supporting marijuana as a controlled substance (i.e. alcohol). While I honestly doubt that research will discover that long term exposure to marijuana will cause harsh, irreversible side effects like smoking cigarettes, there are already side effects that are seen when comparing cognitive faculties of people who have smoked since they were in their teens versus those who smoked after their brain completely matured.
Ultimately my opinion is exactly that, my opinion. It is no more valid, or invalid than anybody else, but ask yourself this: is the risk of being wrong about marijuana in the short term worth the possible side effects about legalizing it before it’s medically better understood?
Alzheimer’s linked to Diabetes
The topic in our Neurochemistry class this past week was Alzheimer’s Disease and how it is linked to Type II Diabetes Mellitus, T2DM. The science behind this link is that if there is either a decreased amount of insulin in the brain or if there is insulin resistance, individuals may develop a neurodegenerative disease, such as Alzheimer’s Disease. Alzheimer’s develops because insulin is essential for memory and learning.
My great-grandmother has struggled with Type II Diabetes for many years. Last year she sent me a birthday card five months after my birthday. My entire family laughed about it, but after learning about this link between T2DM and Alzheimer’s, I am wondering if perhaps she may be developing Alzheimer’s. My dad has also recently developed T2DM, and now I am even more concerned about his future health and the possibility of him eventually developing Alzheimer’s.
When insulin binds to its receptor it can have cognitive and metabolic effects within the brain. The cognitive effects include increased memory and learning, and increased neuronal plasticity. Metabolic effects include decreased food intake, and decreased hepatic glucose production. Alzheimer’s can develop when insulin’s signaling is disrupted. For example, when inflammation occurs insulin signaling is impaired. Although inflammation occurs naturally with age, the inflammation in the brains of individuals with Alzheimer’s is significantly more pronounced.
The most recent drug being developed to treat Alzheimer’s is an intranasal insulin spray called Detemir. This drug has been successful because it has been shown to improve memory in humans. Although this drug may help with symptoms of Alzheimer’s, there is still no cure for Alzheimer’s disease.
Another point to consider is that as a society we are living longer, so maybe Alzheimer’s is only appearing now because we are living longer. Through research, we may find a cure for Alzheimer’s in the future, but until that happens the most important thing we can be doing is educating others about Alzheimer’s and other diseases it is associated with.
References:
http://www.nature.com/npp/journal/v32/n1/full/1301193a.html
Is it time to forget about finding a “cure” for Alzheimer’s disease?
In the last few years I’ve watched my grandmother sink into the mysterious depths of her Alzheimer’s disease. However, as she approaches 90 years old it is not just her mind that is failing, as she struggles to regulate her cardiovascular (heart and blood pressure) and gastrointestinal (stomach, intestines) systems. Therefore, is Alzheimer’s really a disease or is it just a condition that is part of the normal human process of aging?
Although it may be tempting to call it a disease because it isn’t readily apparent in every individual, Alzheimer’s may be considered for classification as part of the aging process, similar to the slowing down and general decline of many other essential organ systems, albeit much more sad. However, much of the focus of aging is on the cognitive and behavioral aspects, perhaps because other organs may be replaced or otherwise supported functionally with treatment, or because there is a general consensus that the essence of a person is in their personality and intellect which disappear with declining mental health. While in the not-so-distant past, Grandma just became increasingly forgetful as she aged, today even the most elderly are subjected to batteries of tests looking for abnormally high levels of forgetfulness in 80 and 90 year olds. Yes, Alzheimer’s in the younger-onset demographic is most likely a disease, but once an individual is at a point where multiple organ systems aren’t functioning properly, forcing them to be on inordinately large numbers of pills per day to simply stay alive, is the mental decline of Alzheimer’s really more of a disease than the natural aging of the rest of the body?
Aging, however, is a complex equation; for example, why do people and their respective organ systems age at different rates? One aspect of rate of aging may be lifestyle. A large lifestyle concern in the US in particular, is obesity and the wide range of disease that accompany overeating and sedentary lifestyle: one of these is type 2 diabetes mellitus (T2DM). There are studies that show a connection between neuronal insulin action (part of T2DM) and the development of Alzheimer’s. This may be driven by inflammation in the central nervous system (CNS), providing the cellular processes contributing to neuroinflammation as a target for research.
Because of the natural aging process that effects the brain, this research should not focus on finding a “cure” for Alzheimer’s, but rather more productive and high-impact aspects of the condition. This is not to say that research should not be undertaken; rather, the research should focus on learning more about the etiology and pathology (for lack of a better term) of Alzheimer’s and comfort of the individual and family during the end of life stages. There should continue to be research for treatment and a possible “cure” for younger-onset versions of Alzheimer’s. Besides, to “cure” Alzheimer’s, we’d have to virtually pause or reverse aging, which is just far too ethically controversial.
ALS: What’s the best approach when the answer is not in your genes?
Amyotrophic lateral sclerosis or ALS is better known as Lou Gehrig’s disease and is a neurodegenerative disease that appears during midlife of an adult. It results in progressive motor neuron loss, making voluntary and eventually even involuntary movement impossible, eventually being fatal. The etiology or cause of ALS is not well understood although there is a focus on studying possible genes involved. This may not be the best approach because only 10% of individuals diagnosed with ALS is considered familial (or with heritable genetic origins) compared to the other 90% being sporadic. Sporadic ALS appears in an individual with no family history of the disease and is not necessarily linked to a heritable gene.
One gene that has been studied extensively (even though there isn’t a strong genetic connection to most ALS cases) is the SOD1 gene. SOD1 stands for superoxide dismutase 1 and is an enzyme (or molecule) in our cells that breaks down dangerous chemicals called reactive oxygen species (ROS) that can cause cells to age prematurely and eventually die. A mutation in the SOD1 gene causes the enzyme not to work properly which leads to an accumulation of ROS in the cell and may cause the cell to age and die from stress.
Mutations in the SOD1 gene are found in about 20% of familial ALS patients and 7% of sporadic ALS patients. Even though these numbers may seem small, they represent the largest percentage of individuals that have a similar mutation, which is why SOD1 is so widely studied. This certain mutation is also how scientists study ALS in animals. The animal model used has the mutant version of SOD1 and shows many of the symptoms of ALS.
This leads to the question: should those individuals diagnosed with ALS and their offspring be required to have genetic sequencing (testing) and counseling? Although ALS may not be consistently genetic, if it could identify even a few individuals who may have the disease early enough on to teach them about the disease before they have their own children it may be worthwhile. However, this broaches many ethical considerations. For example, what if an individual whose parent is diagnosed with ALS does not want to know if their genes are mutated? Is there an ethical responsibility on that individual if they have children even if they know they may be a “carrier” of ALS? Is there an ethical need for these individuals and any possible children to undergo genetic counseling to better understand and process their condition and possibility of fatal disease? Much of the considerations surrounding diseases as devastating as ALS turn out to be ethical, instead of medical, in the end. That is not to say however, that continuing supporting, funding, and doing research on ALS won’t help to elucidate the cause and find new treatments for the disease.
Insulin: impacting more than just diabetes
Those impacted by Alzheimer’s disease (AD) has reached an alarming number of 5 million individuals as of 2015 in the United States alone. AD has no cure, which is why the diagnosis can often be so hard on friends and family. Memory loss, general confusion, and difficulty concentrating characterize the disease, which can all be blamed on the formation of beta amyloid plaques and neurofibrillary tangles in the brain.
But wait, the Title mentioned diabetes, not Alzheimer’s disease. Where is this going?!
Type II diabetes is not categorized as a neurodegenerative disease like AD is. But Type II diabetes itself impacts 90-95% of those diagnosed with any form of diabetes. The disease is characterized with what is called “insulin resistance.” This phenomenon is where the body is unable to properly create enough insulin. Or enough insulin is being produced, but insulin in general is unable to bind to its insulin receptor.
But what in the world does Type II diabetes have to do with AD?
Calm down and let me tell you.
New research is discovering a similarity in the pathways of Type II diabetes and Alzheimer’s disease. The two major pathways have been labeled MAPK and PI3K.
Two of the major problems that differentiate AD from other neurodegenerative diseases are the formation of amyloid beta plaques and neurofibrillary tangles. These plaques and tangles can be traced back to a malfunction of insulin in the PI3K pathway.
Looking exclusively at the PI3K pathway of the cell, neurofibrillary tangles are formed when glycogen synthase kinase 3 beta (GSK3ß) is NOT inhibited. The inhibition of this particular kinase can be traced all the way back to the successful or unsuccessful binding of insulin (refer to yellow circle titled ligand below) to a specific type of receptor tyrosine kinase, in this case an insulin receptor (refer to blue prong-like image below). If insulin is successfully able to bind to its receptor, a series of excitatory or inhibitory signals occurs. As the picture below refers to, a series of excitatory signals must occur in order for GSK3ß to successfully be inhibited. Successful inhibition reduces the amount of protein (specifically tau) phosphorylation.
In a healthy neuron, tau proteins bind and support the microtubules found in the axon of a neuron. Unfortunately, in the case of those with Alzheimer’s disease, if the inhibitory signal is not received to the GSK3ß, the protein tau continues to phosphorylate, causing its normal function in binding and stabilizing microtubules to cease, dissociating the microtubule all together, leading to the neurofibrillary tangles (as can be seen by the image below).
Yes, I get it. This is a lot of information that is very easy to think has completely gone in over the head. Let me try and sum all of this up for you.
Take home message: Insulin is a hormone that plays a very important role in both diabetes and Alzheimer’s disease. Too much or too little insulin is never good. The unfortunate part of all of this is that no one really knows the exact amount of insulin needed in the body for everything to function properly. Insulin, when properly binding, has the ability to inhibit the formation of beta amyloid plaques and neurofibrillary tangles and promote neuronal growth within the brain, which can lead to improvements in cognition.
The question remains: Are those who suffer from Type II diabetes more prone to Alzheimer’s disease, as improper binding of insulin is categorized in both Type II diabetes and Alzheimer’s disease?
The discoveries researchers are finding that show how insulin plays a role in both AD and Type II diabetes will hopefully lead future researchers to something that doesn’t go over everyone’s head:
A cure.
Alzheimers Disease: When Decisions Can't Be Made
Alzheimers disease (AD) is a disease that is very prevalent in the present day. Many people know Alzheimers disease due to its effect on causing people to forget things. Alzheimers disease does in fact cause one to forget many things, but there is much going on inside the body causing this forgetfulness, loss of memory, and overall trouble of thinking. With these problems occurring, another problem usually arises and that is the fact that the patient with Alzheimers disease can no longer speak for themselves and needs a family member to do so for them. This can create many problems which will be talked about. First it is key to understand the science behind Alzheimers disease.
The key reason for Alzheimers disease that is currently under research is the role of insulin in the central nervous system. One possible way that insulin leads to AD is through impaired neuronal insulin action. The big reason impaired neuronal insulin action is bad is that insulin has a regulatory role concerning the amyloid precursor protein and its derivative beta-amyloid. This protein is associated with senile plaques which are seen in high concentration when someone has AD. So when insulin is being impaired, the degradation and trafficking of beta-amyloid is basically being interfered with and that can lead to Alzheimers disease. So possible treatment for Alzheimers disease could be done by administering insulin to a patient with AD. This is still an area that needs much research, but it provides a hopeful option to treatment for AD.
This leads me to talking about the effects that AD can have on a person. When a person gets AD, they start to lose there memory and ability to think. This causes them to often be forgetful. As the disease progresses, this issue becomes worse and often times the person isn’t able to make decisions for themselves any longer. This creates many issues because often the family has to take over for that person. If the patient didn’t set up any type of plan for themselves as far as what they want in a life where they can no longer make decisions, then the family has to step in. This often leads to a patient family conflict. The family can often be selfish when they think they are doing what is best for the patient, but they really just don’t realize what the patient wants and that is not their fault. Often the patient will be in a lot of pain and discomfort and the family will keep trying to do everything in their power to keep that patient alive when maybe the patient doesn’t want that but just can’t express that feeling. This type of issue is very common in the medical field and is one that needs to be addressed. There needs to be some type of program implemented that meets with people early in life to discuss what they want if they happen to be faced with a serious illness. Its not just AD where this issue arises, but many other diseases also see this issue. If a program can be implemented then future family and patient issues could be avoided leading to a happier party of both sides.
Overall Alzheimers disease still needs to have much research done to discover effective treatments for patients experiencing AD, but there are areas that give hope like insulin. There also needs to be a program implemented that will allow patients the opportunity to talk about what they want with their life if they are faced with a serious illness and can no longer make decisions for themselves. If this can be accomplished, then there will be less patient family issues in the medical field.
ALS: is it worthy of the public limelight?
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that kills/damages cells in the brain and the spinal column. The cells that are especially impacted are motor neurons, leading to involuntary muscle spasms. Eventually as the disease progresses control over voluntary muscles begins to decrease, eventually voluntary muscle control is lost. The disease will even claim the person’s ability to live by themselves, feed themselves and ultimately their ability to breathe for themselves. While the person’s physical abilities decrease exponentially the thinking capability of the person remains unimpeded, keeping their mind as sharp as it was previously.
ALS is a disease that affects around 30,000 people in the United States, a relatively rare neurodegenerative disease. Unfortunately global statistics on this disease are much harder to find, a quick search of the Internet leads me to the statistic that 30,000 people in the US are impacted. It is approximately as common as Huntington’s Disease, a degenerative disease that was prominently featured in the TV show House M.D.. While both diseases are incredibly damaging to families and people it is merely a small fraction of the number of people that are killed in the US (and the world) each year. In the United States 2 per 100,000 deaths are by (or are related to) ALS; while 3.5 per 100,000 deaths are related to guns/gun violence (I only use this as a framing device).
This is not meant to belittle the impact of ALS on society, it is merely meant to show how few people it impacts. Until recently I hadn’t heard of the ALS Ice Bucket Challenge (I freely admit I live under a rock when it comes to popular culture), but it surprised me. It’s raising money and awareness for a disease that is devastating and painful to watch a loved one go through; but raising awareness for a disease that impacts a mere 0.01% of the population in the US. When I quickly Googled how much money the Ice Bucket Challenge raised to research a cure for ALS over $15,000,000 (fifteen million) has been raised since it first began.
This begs the question to me: Is such a relatively rare disease deserving of the newfound public fame when diseases like Creutzfeldt-Jakob disease (CJD), a prion disease, impacts 10 people per 100,000 across the globe? In the state of Minnesota alone 13 people per 100,000 (the US as a whole is approximately 9.6 per 10,000) die from CJD with death occurring on average six months after the onset of the disease. While ALS is completely deserving of being researched and funded to the best of their ability there are also other diseases, diseases few people have heard of that impact more people than ALS and are currently without any effective treatments; like CJD.
I will end this blog post with a humble request: next time when the Ice Bucket Challenge scrolls across social media (and I guarantee it will) just remember there are also other diseases that are just as worthy, if not more so, than ALS.