The endocannabinoid system (ECS) is a key modulatory signaling pathway [1]. Which, I’ve heard, is a very common phrase in the scientific community, and is simply a fancy way of saying it does a whole lot of stuff. So what exactly does it modulate, and what does that mean?
The ECS is made up of two major receptors, called CB1 and CB2. CB1 receptors are found primarily in the central nervous system, and CB2 receptors are found in the immune system.
Activation of ECS receptors [1]These receptors are actually found on the presynaptic cell (normally receptors are found on the postsynaptic cell), making them a part of retrograde signalling [1].
The ligands of this system are endogenous cannabinoids, which are produced on demand. An increase of intracellular calcium triggers arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) to be synthesized from the phospholipid bilayer [1].
Starting at the phospholipid bilayer, the enzymes NAPE and PLD are used to make AEA. The enzyme FAAH is used to degrade AEA into AA.
From the phospholipid bilayer, the enzyme PLC is used to make DAG, then the enzyme DAGL is used to make 2-AG. The enzyme MAGL is used to degrade 2-AG into AA.
Once synthesized, these eCB bind to CB1 and CB2 (GPCR receptors), and inhibit adenylyl cyclase. This decreases levels of cyclic-AMP, inhibits calcium channels, and inhibits neurotransmitter release. Overall, when the receptors are activated, they decrease signaling in other pathways [1].
Roles
As we said earlier, the ECS modulates a whole bunch of stuff. Another way of saying that, is the ECS regulates a lot of cellular processes. This means it has a lot of roles, and can change cellular communication and processes in relation to them all. These are some of the processes the ECS modulates:
Endocannabinoids, such as THC, are often used to treat central nervous system diseases including multiple sclerosis, Huntington’s disease, Alzheimer’s disease, epilepsy, anxiety, and depression. THC can be helpful with reducing pain and inflammation, regulating mood, and providing a neuroprotective role against neurodegeneration [1]. However, the ECS is an incredibly complicated system, and long term use of THC does have potential side effects and risks. This can include:
Apathy and passivity, as well as a decrease in motivation and goal-oriented behaviors. This may be due to altered neurocognitive functioning and reward salience [2].
Alterations in learning and memory, and disruptions of long-term potentiation. This is due to changes in glutamatergic neurotransmission signaling [3].
Excitotoxicity due to increased glutamate receptor expression [3].
Neurodegeneration due to too much calcium [3].
Inflammatory cytokine production and inflammationDesensitization [4].due to activation of microglia and astrocytes [3].
Downregulation, receptors permanently being removed, and desensitization, the uncoupling of the G-protein from the receptor. These processes are related to tolerance [4].
Research and Regulations
The gist of it is we do not know enough about the ECS and endocannabinoids work. We need more research in order to be prepared with a more complete explanation of risks and benefits. However, marijuana (the cannabis plant that contains more than 60 active synthetic ligands for CB1 and CB2, including THC), is a schedule 1 drug. This classification is defined with “no currently accepted medical use and a high potential for abuse” despite proven therapeutic benefits [5]. This means in order to study cannabis, there are a lot of regulations and paperwork involved, restricting the amount of research that can be done [6].
With this lack of understanding of the risks, there needs to be more regulations on marijuana. Regulations, not criminalization. For example, making sure kids and their developing brains don’t have access without a medical prescription. Or regulating the marketing and packaging, so colorful bags of gummy bears don’t catch the eyes of an eight year old, who then ends up ingesting 100mg of THC.
People need to be able to make informed decisions, taking into consideration the short-term and long-term impacts on their health. The scientific community needs to be able to do more research, then communicate the results to the public in a way that educates them, but doesn’t tell them what to do. People who rely on endocannabinoids for their medical purposes have a right to understand all the benefits as well as risks. And the general public has the right to be informed to aid in their decision making as well.
References
[1] Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294
[2] Rovai, L., Maremmani, A. G. I., Pacini, M., Pani, P. P., Rugani, F., Lamanna, F., Schiavi, E., Mautone, S., Dell’Osso, L., & Maremmani, I. (2013). Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse. Rivista Di Psichiatria, 48(1), 1–9. https://doi.org/10.1708/1228.13610
[3] Chowdhury, K. U., Holden, M. E., Wiley, M. T., Suppiramaniam, V., & Reed, M. N. (2024). Effects of Cannabis on Glutamatergic Neurotransmission: The Interplay between Cannabinoids and Glutamate. Cells, 13(13), 1130. https://doi.org/10.3390/cells13131130
[4] Piscura, M. K., Henderson-Redmond, A. N., Barnes, R. C., Mitra, S., Guindon, J., & Morgan, D. J. (2023). Mechanisms of cannabinoid tolerance. Biochemical Pharmacology, 214, 115665. https://doi.org/10.1016/j.bcp.2023.115665
[5] U.S. Department of Justice. (n.d.). Drug scheduling. United States Drug Enforcement Administration. https://www.dea.gov/drug-information/drug-scheduling
[6] Medications: Research on schedule I drugs. National Alliance on Mental Illness. (2024, July 23). https://www.nami.org/advocacy/policy-priorities/improving-health/medications-research-on-schedule-i-drugs/#:~:text=Federal%20law%20prohibits%20the%20manufacture,studying%20any%20Schedule%20I%20drugs.
Have you ever smoked weed? If you haven’t, recent research has shown that you may want to consider it, as it may have neuroprotective roles on our body’s neurons.
The Endocannabinoid System (ECS)
The system in the brain that cannabis targets is the endocannabinoid system (ECS). Delta-9-tetrahydrocannabinol, better known as delta-9-THC, is the main ligand, out of around 60 ligands, within marijuana that binds to the ECS’s two receptors: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are concentrated with the brain and spinal cord, while CB2 receptors are more localized in the peripheral nervous system and more directly associated with regulating microglia and inflammation.1
CB1 receptors are G-protein coupled receptors (GPCRs) localized on pre-synaptic membranes of neurons that are activated in the absence of agonists like delta-9-THC. The binding of such agonists to CB1 receptors inhibits Ca2+ outflow from the presynaptic neuron while triggering a temporary increase of intracellular Ca2+ in the post-synaptic neuron. This triggers enzymes NAPE-PLD and DAGL to make arachidonylethanolamine (AEA) and 2-arachidononylglycerol (2-AG), respectively. AEA and 2-AG are the main endocannabinoids that bind to the CB1 receptors, further inhibiting the outflow of calcium and potassium, neurotransmitters release, and production of cAMP by inhibiting adenylyl cyclase. 1 This cycle can be seen in the upper portion of Figure 1.
Figure 1. This shows the pathway that occurs after a ligand, such as delta-9-THC, binds to a CB1 receptor. 1
The lower portion of Figure 1 shows how a protein called B-arrestin is involved in the internalization of CB receptors, which may occur after prolonged exposure to CB1 receptor agonists. The binding of B-arrestins uncouples the G-proteins of the CB1 receptor and stimulates internalization, leading to a tolerance to endocannabinoids.1 For more information on the pathways of the ECS, click here.
And that tolerance may be what you think of when you think of people becoming addicted to smoking weed. But what positive effects can occur when you consume cannabis or delta-9-THC?
How Endocannabinoids Are Protective
Well, the endocannabinoid lipid molecules similar to AEA, such as palmitoylethanolamide (PEA) and N-oleoylethanolamide (SEA), have been shown to anti-inflammatory and neuroprotective actions. PEA and SEA do this by inhibiting fatty acid amid hydrolase (FAAH) and monoacylglycerol (MAGL), the enzymes that degrade AEA and 2-AG, respectively. With increased levels of AEA and 2-AG, neurodegeneration is prevented. Considering a mouse study where mice were treated with SEA, 2-AG levels were increased before an increase of CB receptor expression, confirming that SEA interferes with the ECS system.2
But what makes the increase of 2-AG and AEA neuroprotective? One role to consider is that of microglia, which play a large role in neuroprotection. Microglia have CB2 receptors on them, and chronic activation is generally considered detrimental for neuronal health. Since 2-AG and AEA are inverse agonists of the ECS in microglia, they inhibit their activation, decreasing prolonged microglial immunoreactivity, therefore protecting neurons from being unnecessarily degraded. 2 For more information regarding what PEA and SEA do, look at Figure 2 or click here.
Figure 2: This illustrated the neuroprotective effects that AEA, PEA, and SEA have on neurons. 1
Aside from microglia, astrocytes also play a large role in neuroprotection. Similar to microglia, astroglial CB1 and CB2 receptors play critical roles in inflammatory responses, with activation of these receptors protecting neurons against oxidative stress, apoptosis, and nitric oxide. 2
Endocannabinoids & Neurodegenerative Diseases
Looking at neurodegenerative diseases, is has been shown that CB2 receptors and FAAH are overexpressed during Alzheimer’s disease, leading to neurotic plaque buildup in astrocytes and microglia. Administration of MAGL and FAAH inhibitors led had anti-inflammatory effect on these glial cells, reducing amyloid-beta deposition. The ECS system has also been shown to have positive effects on dopaminergic neurons in Parkinson’s disease and neuronal regeneration in multiple sclerosis. Therefore, the ECS, cannabis, and delta-9-THC have the potential to treat neurogenerative disease and stimulate neuroprotection within the brain. 2 For more information on that, click here.
Conclusion
In conclusion, microglia and astrocytes are coupled to functions related to inflammatory production, pro-survival changes, resolution of neuroinflammation, and protection from toxic metabolites. The contribution of eCB signaling is relevant to protection of neurons, and further research should be done to determine whether the use of medical marijuana can effectively target neurodegenerative diseases without significant negative side effects. If that research is promising, it may suggest that cannabis be used as a preventative treatment for such diseases, promoting its use by the general population.
Footnotes
1Kendall, D., Yudowski, G. “Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.” Frontiers in Cellular Neuroscience, vol. 10, no. 294, 2017, pp. 1-10, doi: 10.3389/fncel.2016.00294.
2Kasatkina, L.A., et. al. “Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation.” International Journal of Molecular Sciences, vol. 22, 2021, pp. 1-35, https://doi.org/10.3390/ijms22115431.
The article “Insulin Signaling Pathway and Related Molecules: Role in Neurodegeneration and Alzheimer’s Disease” explores how insulin dysfunction contributes to the development of neurodegenerative disorders, particularly Alzheimer’s Disease (AD). It highlights key pathways, including insulin resistance, neuroinflammation, and oxidative stress, and their roles in neuronal damage.
Neurodegenerative illnesses, particularly Alzheimer’s disease (AD), are an increasing public health concern, affecting millions of people worldwide. Understanding and addressing the molecular pathways that cause neuronal damage is critical for reducing these disorders. One such crucial mechanism is the Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2) signaling system, which is the primary regulator of the body’s antioxidant response. According to emerging research, Nrf2 has an important role in countering oxidative stress and insulin resistance, both of which contribute to neurodegeneration and cognitive decline. Scientists hope that by unleashing Nrf2’s therapeutic potential, they will be able to develop therapies that will reduce or prevent diseases like Alzheimer’s.
Nrf2 is a transcription factor that controls the production of numerous antioxidant and detoxification enzymes, thereby protecting cells from oxidative damage. Under normal physiological settings, Keap1 (Kelch-like ECH-associated protein 1) inhibits Nrf2, allowing it to degrade. However, when exposed to oxidative stress, Nrf2 is produced, translocates to the nucleus, and activates protective genes . According to research, dysregulated Nrf2 signaling leads to Alzheimer’s disease progression by aggravating oxidative stress and increasing insulin resistance. Studies have indicated that a drop in Nrf2 activity is connected with increased oxidative damage in neurons, resulting in protein misfolding, neuroinflammation, and eventually neuronal death . Furthermore, Nrf2 has been shown to interact with insulin signaling pathways. Inhibiting Nrf2 decreases the phosphorylation of Akt, which is a crucial regulator of glucose metabolism and neuronal survival. This disruption adds to insulin resistance, which is not just a hallmark of diabetes but also connected to cognitive decline and Alzheimer’s disease progression.
How Do We Activate Nrf2 for Brain Health?
Given its protective effect, therapeutic stimulation of Nrf2 is a promising therapy for neurodegenerative disorders. Several approaches include:
Pharmacological activation: Certain substances, including as sulforaphane (found in broccoli), curcumin (from turmeric), and synthetic Nrf2 activators, can boost Nrf2 signalling and enhance antioxidant defenses.
Inhibiting GSK-3β may boost Nrf2 activation, making it a possible therapeutic target for Alzheimer’s disease.
Insulin signaling pathway
Insulin signaling pathway and the role of its molecules in neurodegeneration and AD has been described in the following paragraphs Fig. 1 .
Fi.1. Role of insulin and its binding to receptor, role of various molecules in the insulin signaling pathway and subsequent role in neurodegeneration and Alzheimer’s disease.
Nrf2 and Insulin Signaling
Nuclear factor erythroid-2-related factor 2 (Nrf2) is a basic leucine protein that regulates antioxidant protein expression. Cells express it ubiquitously and constitutively. Under normal physiological settings, it is constantly destroyed by the ubiquitin proteasome system, and low Nrf2 levels result in basal expression of its target genes. The E3 ligase adaptor Kelch-like ECH-associated protein 1 (KEAP 1) regulates Nrf2 stability
Nrf2 is a novel and very promising target in many neurodegenerative diseases including AD. Neurodegeneration involving oxidative stress and insulin resistance can be alleviated by targeting the Nrf2 pathway. Inhibitors of GSK3 can activate Nrf2 signaling as they are likely to blunt βTrcP-mediated degradation and impede nuclear exclusion of Nrf2. The same applies to compounds activating MAPK (ERK, JNK, and p38) signaling( Zhang et al., 2014) (Fig. 2).
Fig. 2. Involvement of Nrf2 in oxidative stress and insulin resistance through keap1, GLUT4, PI3K/Akt.
With an aging global population, the burden of neurological illnesses is likely to increase. Targeting the Nrf2 pathway could lead to significant advances in neuroprotection and disease prevention. By deepening our understanding of this system, we can pave the road for novel treatments that may one day slow or even reverse cognitive decline. Incorporating Nrf2-boosting techniques, such as dietary changes and exercise, could be a proactive approach to brain health. Furthermore, ongoing investment in research and clinical trials is critical for converting these results into viable medicines.
In a nutshell, malfunction and anomalies in the insulin signaling system and related components may contribute to the neurodegenerative process that characterizes Alzheimer’s disease. Several studies found that manipulation of components downstream in the insulin signaling cascade enhanced insulin sensitivity. It can also be concluded that there is a substantial relationship between neuroinflammation and insulin resistance. Diabetes mellitus and Alzheimer’s disease share characteristics such as insulin resistance and inflammation. Furthermore, insulin resistance has been linked to other neurodegenerative disorders such as Parkinson’s and Huntington’s disease.
As a result, from a therapeutic standpoint, improving the insulin signaling system by modulating its components can slow neurodegeneration and alleviate illness symptoms.
References
Akhtar, A., & Sah, S.P. (2020). “Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease.” Neurochemistry International. DOI: 10.1016/j.neuint.2020.104707.
Morrison, C.D., et al. (2010). “High-fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling.” Journal of Neurochemistry. DOI: 10.1111/j.1471-4159.2010.06609.x.
Suzuki, T., & Yamamoto, M. (2015). “Molecular basis of the Keap1-Nrf2 system.” Free Radical Biology and Medicine. DOI: 10.1016/j.freeradbiomed.2014.12.017
Park, J.G., et al. (2016). “Indirect activation of Nrf2 by AMPK and PI3K/Akt signaling pathways.” Antioxidants & Redox Signaling. DOI: 10.1089/ars.2016.6778
Alzheimer’s disease and Polycystic Ovarian Syndrome (PCOS) are two seemingly unrelated conditions that disproportionately affect women. Alzheimer’s, a devastating neurodegenerative disease causing symptoms such as memory loss and cognitive decline, is the leading cause of dementia and affects over twice as many women as men[1]. PCOS, on the other hand, is a common hormonal disorder that impacts 1 in 10 women of reproductive age, causing symptoms like irregular periods, weight gain, and fertility issues[2]. While these conditions appear distinct, emerging research suggests they may be linked by a shared underlying mechanism: metabolic dysfunction.
What is “Type III Diabetes”?
The term “Type III Diabetes” describes the link between insulin resistance in the brain and Alzheimer’s disease. The 2020 review “Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s Disease” highlights how impaired insulin signaling in the brain contributes to the accumulation of amyloid plaques and tau tangles, leading to Alzheimer’s disease progression[3].
Insulin resistance is also a key feature of PCOS. Women with PCOS often struggle with metabolic issues, including difficulty regulating blood sugar, weight gain, and a highly increased risk of Type II Diabetes[4]. This overlap raises an important question: Could the metabolic dysfunction seen in PCOS increase the risk of Alzheimer’s disease in women?
Understanding PCOS
PCOS is a complex hormonal disorder that affects the ovaries and the body’s ability to regulate androgens. Common symptoms include irregular menstrual cycles, excess hair growth, acne, and ovarian cysts. PCOS also impacts metabolism, inflammation, and even brain health.
One of the noted features of PCOS is insulin resistance. Additionally, women with PCOS often have imbalances in estrogen and progesterone, hormones that play a protective role in brain health[4]. These hormonal and metabolic irregularities may potentially lead to the pathogenesis of neurodegenerative diseases like Alzheimer’s.
The Overlapping Science
The connection between Alzheimer’s and PCOS lies in their shared biological and pathological mechanisms. Both conditions are characterized by insulin resistance, chronic inflammation, and hormonal imbalances, all of which can negatively impact brain health.
Insulin Resistance: When the body becomes resistant to insulin, it struggles to regulate blood sugar levels, leading to elevated insulin and glucose in the bloodstream. Insulin resistance is associated with increased production and reduced clearance of amyloid-beta plaques. Insulin-degrading enzyme helps to clear these plaques but is less effective when a person is insulin-resistant. Amyloid-beta plaques also bind to insulin receptors, thus further exacerbating insulin resistance. Insulin resistance can activate kinases that hyperphosphorylate tau proteins, causing them to form neurofibrillary tangles. These plaques and tangles are hallmarks of Alzheimer’s and cause cell death in the brain[3].
The mechanism of insulin resistance and other symptoms in PCOS [4].
The relationship between PCOS and insulin resistance is complex and bidirectional, meaning they can influence each other in a cyclical manner. It’s not entirely clear which comes first, as both conditions are intertwined and can exacerbate one another. Elevated insulin levels directly affect the ovaries by producing more androgens and reducing the liver’s production of sex hormone-binding globulin, increasing the levels of free androgens in the bloodstream. Insulin resistance can also disrupt the hypothalamic-pituitary-ovarian axis, leading to hormonal imbalances that further exacerbate PCOS symptoms. In turn, hyperandrogenism from PCOS alters fat distribution and impairs glucose metabolism, causing insulin resistance[4].
Inflammation: Chronic, systemic inflammation is a key feature of both conditions, likely exacerbated by insulin resistance. In PCOS, inflammation is driven by metabolic dysfunction and elevated androgens. Studies have found increased levels of inflammatory markers, such as cytokines and c-reactive proteins, in women with PCOS[4], [5].
Neuroinflammatory pathway in Alzheimer’s disease [6].
In Alzheimer’s, inflammation in the brain exacerbates neurodegeneration. As mentioned earlier, tau and amyloid-beta aggregation are hallmarks of Alzheimer’s. The presence of tau and amyloid-beta activates glial cells, which act as support and immune cells in the brain. These glial cells become chronically activated, which triggers the release of pro-inflammatory cytokines and reactive oxygen species[3]. The elevated levels of inflammatory markers in both PCOS and Alzheimer’s may suggest a shared inflammatory pathway.
Hormonal Imbalances: Estrogen, a hormone often imbalanced in PCOS, plays a protective role in brain health. It helps regulate glucose metabolism, reduces inflammation, and supports the growth and survival of neurons. Women with PCOS may experience fluctuations in estrogen levels, which could increase their vulnerability to Alzheimer’s, especially after menopause when estrogen levels decline[2].
Is PCOS a Risk Factor for Alzheimer’s?
While the exact relationship between PCOS and Alzheimer’s is currently being studied, there is growing evidence to suggest that women with PCOS may be at higher risk for cognitive decline later in life. A recent study found that women with PCOS performed worse on memory and cognitive tests compared to women without the condition, likely due to the increase in androgens[7]. Additionally, the metabolic and hormonal disruptions seen in PCOS (such as insulin resistance, inflammation, and hormone imbalance) are all known risk factors for Alzheimer’s[3]. While these studies begin to illustrate the relationship, future research should focus on the directionality of the links between insulin resistance, PCOS, and Alzheimer’s.
The connection between Alzheimer’s disease and Polycystic Ovarian Syndrome highlights the complex interplay between metabolism, hormones, and brain health. By understanding the shared mechanisms underlying these conditions (particularly insulin resistance and inflammation) we can develop more effective strategies for prevention and treatment. For example, metformin, a commonly used drug used to treat insulin resistance in women with PCOS, is being explored as a potential treatment for Alzheimer’s[3]. As research continues to uncover the links between PCOS and Alzheimer’s, it’s clear that addressing metabolic health is not just a matter of managing symptoms but a critical step in protecting women’s long-term brain health. “Type III Diabetes” serves as a powerful reminder that the health of the body and the brain are deeply interconnected and that women’s health deserves greater attention, investment, and education.
References
[1] M. M. Mielke, “Sex and Gender Differences in Alzheimer’s Disease Dementia,” Psychiatr. Times, vol. 35, no. 11, pp. 14–17, Nov. 2018.
[2] R. Deswal, V. Narwal, A. Dang, and C. S. Pundir, “The Prevalence of Polycystic Ovary Syndrome: A Brief Systematic Review,” J. Hum. Reprod. Sci., vol. 13, no. 4, pp. 261–271, 2020, doi: 10.4103/jhrs.JHRS_95_18.
[3] A. Akhtar and S. P. Sah, “Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease,” Neurochem. Int., vol. 135, p. 104707, May 2020, doi: 10.1016/j.neuint.2020.104707.
[4] A. Purwar and S. Nagpure, “Insulin Resistance in Polycystic Ovarian Syndrome,” Cureus, vol. 14, no. 10, p. e30351, doi: 10.7759/cureus.30351.
[5] S. Aboeldalyl, C. James, E. Seyam, E. M. Ibrahim, H. E.-D. Shawki, and S. Amer, “The Role of Chronic Inflammation in Polycystic Ovarian Syndrome—A Systematic Review and Meta-Analysis,” Int. J. Mol. Sci., vol. 22, no. 5, p. 2734, Mar. 2021, doi: 10.3390/ijms22052734.
[6] M. A. Rather et al., “Inflammation and Alzheimer’s Disease: Mechanisms and Therapeutic Implications by Natural Products,” Mediators Inflamm., vol. 2021, no. 1, p. 9982954, 2021, doi: 10.1155/2021/9982954.
[7] M. Perović, K. Wugalter, and G. Einstein, “Review of the effects of polycystic ovary syndrome on Cognition: Looking beyond the androgen hypothesis,” Front. Neuroendocrinol., vol. 67, p. 101038, Oct. 2022, doi: 10.1016/j.yfrne.2022.101038.
Alzheimer’s and Type 2 Diabetes might be linked, but let’s break down what this means.
The Science Behind Alzheimer’s
Alzheimer’s Disease is characterized by plaques and tangles of proteins clumping up our brain. These plaques are an accumulation of the protein Amyloid-β and are found near neurons, the main cells in our brain. The tangles are from tau proteins accumulating in the neurons. [1] The plaques and tangles can disrupt important communication in our brain and even lead to cell death. This cell death will cause the individual to have problems with cognition and memory because fewer cells are working in the brain.
[2]Both the tangles and plaques can develop for a variety of reasons, but new findings suggest that insulin resistance might quicken the development of these harmful biomarkers.
Insulin Resistance
Insulin resistance is the inability of our body to use insulin, even if insulin is present. This may sound familiar if you or a loved one has Type 2 Diabetes. In this type of diabetes, insulin may be present, but the body doesn’t use it. How is this linked to Alzheimer’s?
Figure 1: The link between insulin dysfunction, obesity/DM, and AD. [3]In Figure 1, insulin at normal functioning is important for breaking down glucose, the main sugar metabolized for energy. Insulin also protects from plaques and tangles forming in our brains, and against cell death in brain areas that are focused on learning and memory. All of which is important for protection against Alzheimer’s.
When Type 2 Diabetes sets in, our body starts to resist insulin. The causes of diabetes and insulin resistance will be discussed later. Since insulin is no longer being used, our protection against plaques and tangles decreases. Not only this, but diabetes can lead to increased inflammation due to fat sending inflammatory signals.
Inflammation, along with neuroinflammation (inflammation in the brain and spinal cord), can contribute to further insulin resistance to create a vicious cycle of worsening the body’s responses to insulin.
Since insulin is no longer protecting against plaques and tangles, cell death in learning and memory brain areas, and breaking down glucose, the brain may be at a higher risk for Alzheimer’s Disease.
Early treatments are being tested in which Alzheimer’s patients take Diabetes medications, and they have seen some cognitive benefits in those patients. More research is needed to fully understand the possible link between Alzheimer’s and Diabetes, but as a precautionary note, let’s examine some risk factors for insulin resistance developing.
Causes of Insulin Resistance and Type 2 Diabetes
Some causes of Type 2 Diabetes are out of our control, such as genetic make-up and family history. Our genes can determine if we’re more or less sensitive to insulin. [4]
Out of the modifiable factors, obesity is the strongest risk factor for developing Type 2 Diabetes. Increased abdominal fat can lead to more inflammation, which is harmful to insulin signaling. Additionally, an unhealthy diet and low physical activity can lead to Type 2 Diabetes. [5]
[6]Considering the possible tie to Type 2 Diabetes and Alzheimer’s Disease, it’s important to maintain healthy habits to prevent insulin resistance from developing. It’s also important to note that those with Type 2 Diabetes are not guaranteed to get Alzheimer’s. Though for everyone, healthy habits could be a method of protection against Diabetes and Alzheimer’s.
References
[1] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707
[2] Image from Pixabay.
[3] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707
[4,5] Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of Type 2 Diabetes Mellitus. International journal of molecular sciences, 21(17), 6275. https://doi.org/10.3390/ijms21176275
The Brain Needs Fuel—But What If It Can’t Get Enough?
Your brain is a powerhouse, consuming about 20% of your body’s energy despite making up only 2% of your total weight. It runs primarily on glucose, which is delivered by specialized proteins called glucose transporters (GLUTs). These molecular regulators guarantee that neurons obtain the necessary energy to operate effectively.
And for decades, scientists have understood that glucose metabolism plays a very important role in brain well-being. But what happens when those transporters fail? Could this be a hidden trigger for neurodegenerative diseases like Alzheimer’s?
Therefore, recent research suggests that problems with glucose transport may play a role in Alzheimer’s disease, highlighting both a risk and a possible new treatment approach.[1]
The Science: How Glucose Transport Breakdown Fuels Alzheimer’s
Your brain runs on glucose, but neurons can’t just absorb it freely from the bloodstream. They rely on glucose transporters, mainly:
GLUT1 – The gatekeeper at the blood-brain barrier (BBB), moving glucose from the bloodstream into the brain.
GLUT3 – The main supplier inside the brain, delivering glucose directly to neurons.
Step 1: The Energy Crisis Begins
In Alzheimer’s disease, researchers have found that levels of GLUT1 and GLUT3 drop significantly [2]. This means less glucose gets into the brain, and even the glucose that does enter has trouble reaching neurons.
Think of your brain like a power grid:
GLUT1 is the main power line bringing electricity to the city (brain), but it’s weakening.
GLUT3 is the wiring that distributes electricity to homes (neurons), but the circuits are failing.
Without power, the homes go dark, and neurons struggle to function.
Step 2: Neurons Under Stress → Synapse Failure
Without enough glucose:
Mitochondria (the cell’s power plants) struggle – They can’t generate enough ATP (energy), which neurons desperately need to function.
Synapses weaken – Since neurons can’t fire properly, memory and cognitive function decline.
At this point, many Alzheimer’s symptoms like memory loss and confusion start to appear.
Step 3: The Vicious Cycle – Amyloid Plaques & Tau Tangles
Now, the brain is in crisis mode, and things get worse:
Beta-amyloid plaques: The brain begins accumulating clumps of beta-amyloid protein, which further disrupts neurons and damages glucose transport.
Tau tangles: Another toxic protein, tau, builds up inside neurons, disrupting their internal transport system.[3]
Inflammation increases: The brain’s immune cells, microglia, respond to the damage by releasing inflammatory molecules such as cytokines and reactive oxygen species (ROS).
While this response is meant to help, it can backfire. Prolonged or excessive inflammation can:
Disrupt energy production: Inflammatory signals interfere with glucose metabolism, worsening the energy shortage.
Damage neurons: Chronic inflammation leads to oxidative stress, which harms neurons and weakens their ability to function properly.
Alter communication: Inflammation can disrupt synaptic connections, affecting memory, cognition, and overall brain function. [4]
Step 4: Insulin Resistance – The “Type 3 Diabetes” Theory
Research suggests that Alzheimer’s disease (AD) shares key similarities with diabetes, particularly in how the brain processes glucose, sometimes being called “Type 3 Diabetes.”
Here’s how insulin resistance plays a role:
Insulin and the Brain: Insulin is important for glucose metabolism and also supports neuron growth, repair, and communication. In a healthy brain, insulin helps regulate energy use and protects against oxidative stress and inflammation.
Insulin Resistance Develops: Just like in Type 2 diabetes, the brain’s cells become less responsive to insulin, making it harder to absorb and use glucose for energy.
GLUT Levels Drop: Insulin resistance leads to a further decline in GLUT1 and GLUT3 transporters, worsening the energy shortage in neurons.
Cognitive Decline: Without enough energy, neurons struggle to function, leading to issues with memory, thinking, and overall brain health.
Can We Fix the Problem? Potential Therapies
Understanding the breakdown of glucose transport in the brain has led to promising treatment strategies that could slow, prevent, or even reverse cognitive decline. Here are some of the most promising approaches:
Medications to Boost GLUT1 and GLUT3
Researchers are developing experimental drugs aimed at increasing the levels or function of GLUT1 and GLUT3 to restore proper glucose transport. Potential strategies include:
Insulin-sensitizing drugs: Medications like metformin or intranasal insulin are being studied for their ability to improve brain glucose metabolism.
Anti-inflammatory treatments: Since inflammation worsens insulin resistance, reducing brain inflammation could help restore glucose transport.
Ketogenic Diets – An Alternative Fuel Source
The ketogenic (keto) diet has gained attention as a potential therapy because it provides an alternative energy source:
Why it works: When glucose transport is impaired, ketones can fuel brain cells even when neurons struggle to use glucose.
Evidence: Some studies suggest that ketones improve cognitive function, memory, and brain energy metabolism in people with mild cognitive impairment or early Alzheimer’s.[5]
Challenges: While promising, the keto diet can be difficult to maintain and may not work for everyone.
Exercise & Cognitive Training – Boosting Brain Metabolism
Both physical exercise and mental stimulation have been shown to increase glucose metabolism and support brain health:
Exercise: Regular physical activity improves insulin sensitivity, reduces inflammation, and increases brain-derived neurotrophic factor (BDNF), which supports neuron survival.[6]
Cognitive training: Activities like puzzles, learning new skills, or social engagement help stimulate brain activity, potentially enhancing glucose metabolism and delaying cognitive decline.
Footnotes
[1] Szablewski L. (2017). Glucose Transporters in Brain: In Health and in Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD, 55(4), 1307–1320. https://doi.org/10.3233/JAD-160841
[2] Kumar, V., Kim, S. H., & Bishayee, K. (2022). Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions. International journal of molecular sciences, 23(17), 9540. https://doi.org/10.3390/ijms23179540
[3] Medeiros, R., Baglietto-Vargas, D., & LaFerla, F. M. (2011). The role of tau in Alzheimer’s disease and related disorders. CNS neuroscience & therapeutics, 17(5), 514–524. https://doi.org/10.1111/j.1755-5949.2010.00177.x
[4] Simpson, D. S. A., & Oliver, P. L. (2020). ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease. Antioxidants (Basel, Switzerland), 9(8), 743. https://doi.org/10.3390/antiox9080743
[5] Rusek, M., Pluta, R., Ułamek-Kozioł, M., & Czuczwar, S. J. (2019). Ketogenic Diet in Alzheimer’s Disease. International journal of molecular sciences, 20(16), 3892. https://doi.org/10.3390/ijms20163892
[6] Connor, B., Young, D., Yan, Q., Faull, R. L. M., Synek, B., & Dragunow, M. (1997). Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Molecular Brain Research, 49(1–2), 71–81. https://doi.org/10.1016/S0169-328X(97)00125-3
Alzheimer’s is a neurodegenerative disease that falls under the broader category of dementia. Symptoms include impaired cognitive function, changes in behavior, and difficulties completing day-to-day tasks. AD most commonly impacts elderly individuals and its development can be divided into 3 stages.[1]
Early Symptoms
Forgetting recent conversations or eventsFigure 1 [2]
Misplacing items
Forgetting the names of places or objects
Frequent tip-of-the-tongue episodes
repeating questions.
[1]
Middle stage symptoms
increased confusion and disorientation
delusions
paranoia
Frequent mood swings
difficulties with spatial tasks
short and long-term memory issues
[1]
Late stage symptoms
loss of speech
incontinence
significant short and long-term memory issues
difficulties with eating and swallowing.
[1]
Mechanisms
Amyloid beta
Amyloid beta is cut from a large protein called amyloid precursor protein by the enzymes beta and gamma-secretase. When created, the individual amyloid molecules called monomers can group up to form a variety of shapes as seen in Figure 2. Amyloid beta oligomers are small and water soluble allowing them to bind receptors and disrupt their functioning. Amyloid beta mature fibrils are large insoluble molecules that can stick together and form plaques that can clog axons and disrupt neuron function.[3]
Figure 2 [2]
Nuerofibrilary tangles
Neurofibrillary tangles form as a result of tau hyperphosprolation. Tau is a membrane-associated protein that helps keep microtubules organized. Phosphorylation refers to the addition of phosphate molecules and when Tau becomes hyperphosphorylated it separates from the microtubules causing them to get tangled. [4]
Insulin resistance
Insulin is a hormone that is secreted by pancreatic cells and cells in the brain. Insulin plays a role in the toxicity of amyloid beta and the formation of neurofibrillary tangles. Insulin is regulated in the brain by the enzyme Insulin-degrading enzyme. A lack of this enzyme can contribute to amyloid beta accumulation and excess insulin levels. Increased brain insulin can also hinder the clearance of amyloid beta, worsening AD pathology. Because of insulin’s role in Alzheimer’s, The disease has been called type 3 diabetes.[3]
Treatment and Prevention
Alzheimer’s is a difficult disease to manage because pathology exists many years before symptoms show. Despite this treatments do exist and while there is no cure, relief can happen.
Medications
Memantine is an NMDA agonist and works by regulating the amount of glutamate in the brain. Glutamate is an excitatory neurotransmitter that can cause a condition called excitotoxicity. In this condition, the excessive excitatory signaling triggers the cell to take in too much calcium which does damage to the cell. Limiting the amount of glutamate and by connection the amount of excitatory signaling, excitotoxicity can be limited. The medication is prescribed for people in the middle to late stages of Alzheimer’s to help mediate symptoms. [5]
Prevention
Alzheimer’s is a very complex disease with a network of causes. Because of this complexity, There is no true way to prevent it but the evidence does show that some behaviors are correlated with lower rates of Alzheimer’s development. The Mediterranean diet which is rich in fruit, vegetables, legumes, whole grains, and monounsaturated fats like olive oil has been linked with improved cognition in individuals at risk of vascular diseases. It also helps reduce the risk of type 2 diabetes. Because both type 2 diabetes and Alzheimer’s seem to involve an issue with insulin resistance this diet could aid in Alzheimer’s prevention. [6]
[1] Graff-Radford, J. (2024, September 25). Alzheimer’s prevention: Does it exist? NHS choices. https://www.nhs.uk/conditions/alzheimers-disease/symptoms/
[2] Pace Hospitals. (2024b, December 10). Alzheimer’s disease – symptoms, causes, types and treatment. Pace Hospitals | Best Hospitals in Hyderabad, Telangana, India. https://www.pacehospital.com/alzheimers-disease-symptoms-types-causes-prevention-and-treatment
[3] Akhtar, A., & Pilkhwal Sah, S. (2020, February 18). Insulin signaling pathway and related molecules: Role in neurodegeneration and alzheimer’s disease. Neurochemistry international. https://pubmed.ncbi.nlm.nih.gov/32092326/
[4]Duan, Y., Dong, S., Gu, F., Hu, Y., & Zhao, Z. (2012, December 15). Advances in the pathogenesis of alzheimer’s disease: Focusing on tau-mediated neurodegeneration – translational neurodegeneration. BioMed Central. https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/2047-9158-1-24
[5] NIH. (2023, September 12). How is alzheimer’s disease treated? | National Institute on Aging. How Is Alzheimer’s Disease Treated? https://www.nia.nih.gov/health/alzheimers-treatment/how-alzheimers-disease-treated
[6] Graff-Radford, J. (2024, September 25). Alzheimer’s prevention: Does it exist? NHS choices. https://www.nhs.uk/conditions/alzheimers-disease/symptoms/
Imagine your brain as a city, with neurons acting like workers who keep everything running smoothly. For these workers to do their job—helping you think, remember, and move—they need energy. Insulin, a hormone that helps control sugar levels, is like the key that unlocks fuel for these workers. But when something goes wrong with insulin, the whole city starts falling apart.
The Role of Insulin in Brain Health
Insulin plays a crucial role in brain function, influencing memory, cognition, and overall neural health. In a healthy brain, insulin supports synaptic plasticity, enhances neuronal survival, and regulates energy metabolism. However, when insulin signaling is impaired, as seen in insulin resistance, it can contribute to neurodegeneration and cognitive decline.
One of the major consequences of insulin resistance in the brain is its impact on the formation of neurofibrillary tangles (NFTs) and amyloid-beta (Aβ) plaques, two hallmarks of Alzheimer’s Disease (AD). Insulin resistance leads to increased oxidative stress and inflammation, which in turn activate kinases such as GSK-3β. This enzyme plays a central role in hyperphosphorylating tau proteins, leading to the formation of NFTs that disrupt neuronal communication and eventually cause cell death.
Additionally, insulin plays a role in regulating the clearance of Aβ peptides from the brain. Under normal conditions, insulin-degrading enzyme (IDE) helps break down Aβ, preventing it from accumulating. However, when insulin levels are chronically elevated due to insulin resistance, IDE becomes increasingly occupied with degrading insulin rather than Aβ. This imbalance leads to an accumulation of toxic Aβ plaques, further exacerbating neurodegeneration.
Moreover, insulin resistance can disrupt the function of GLUT4, a glucose transporter critical for neuronal energy metabolism. Impaired glucose uptake deprives neurons of essential energy, leading to synaptic dysfunction and cognitive impairment.
Studies have shown that insulin administration, either peripherally or intranasally, can enhance memory and cognitive function by improving glucose metabolism, reducing tau phosphorylation, and aiding in Aβ clearance. This suggests that therapies targeting insulin signaling pathways may hold promise in preventing or slowing the progression of AD.
Overall, maintaining insulin sensitivity through lifestyle interventions such as regular exercise, a balanced diet, and metabolic health optimization can significantly reduce the risk of AD and support overall brain function. [1]
[1]
Why This Matters for Alzheimer’s, Parkinson’s, and Huntington’s
Alzheimer’s Disease (AD):
Insulin normally prevents the buildup of toxic proteins like amyloid plaques and tau tangles (which clog up brain cells like roadblocks in a city).
Without insulin’s help, these roadblocks grow, leading to memory loss and cognitive decline.
Parkinson’s Disease (PD):
The brain region responsible for movement, the substantia nigra, depends on insulin to keep dopamine levels balanced.
When insulin resistance occurs, dopamine-producing cells die, causing tremors, stiffness, and difficulty moving.
Huntington’s Disease (HD):
Insulin helps control energy production and repair damaged cells.
In Huntington’s, insulin signaling is disrupted, leading to motor problems and brain cell degeneration.
The Role of Genetics in Alzheimer’s Disease
While lifestyle factors like diet and exercise play a big role in brain health, genetics can also increase the risk of developing AD. One of the biggest genetic risk factors is a gene called APOE (Apolipoprotein E), particularly the APOE4 variant.
People with one copy of APOE4 have an increased risk of AD.
Those with two copies (one from each parent) have an even higher risk and may develop symptoms earlier.
On the other hand, people with the APOE2 variant seem to have a lower risk.
Other genes involved in brain inflammation, insulin signaling, and tau protein regulation also play a role, but having a high-risk gene does not mean someone will definitely get AD. It just means they need to be extra careful with lifestyle choices to reduce their risk. [2]
Reducing the Risk of Alzheimer’s
Even if someone has a genetic risk for AD, behavioral changes can significantly lower the chances of developing the disease. Research suggests the following as ways of reducing the risk of Alzheimer’s:
Keep Blood Sugar and Insulin in Check
Avoid processed foods, sugary drinks, and excessive refined carbs, as they contribute to insulin resistance.
Eat a Mediterranean or low-carb diet, rich in healthy fats (olive oil, nuts, fish) and antioxidants. [3]
Stay Physically Active
Exercise increases insulin sensitivity, reduces inflammation, and boosts brain-derived neurotrophic factor (BDNF), which helps grow new brain cells.
Aim for at least 150 minutes of moderate exercise per week (walking, swimming, or strength training).
Improve Sleep Quality
Sleep removes toxins from the brain, including harmful amyloid proteins linked to AD.
Stick to a consistent sleep schedule and avoid screens before bedtime.
Reduce Stress and Inflammation
Chronic stress increases cortisol, which contributes to brain damage.
Practice meditation, yoga, or deep breathing to reduce stress hormones.
Stay Mentally and Socially Active
Challenge your brain with reading, puzzles, or learning a new skill.
Social engagement reduces inflammation and keeps the brain stimulated. [4]
Consider Fasting or Time-Restricted Eating
Intermittent fasting or time-restricted eating (12-16 hours of fasting overnight) helps regulate insulin and may support brain function. [3]
It should be noted that these are all examples of things that every person should try to aim for to remain healthy. However, this is not an exhaustive list and it is also important that we do not stress over the mere possibility of becoming sick with a disease so much that we cannot live our lives.
[5]
Can Insulin Be a Solution?
The good news is that boosting insulin sensitivity—either through medications, lifestyle changes, or natural compounds—could slow down or even prevent these diseases. Exercise, a healthy diet, and certain drugs that activate the Nrf2 pathway or insulin receptors could help protect brain cells, reduce inflammation, and restore lost function. [1]
Final Thoughts
Your brain and body are deeply connected, and problems like insulin resistance and inflammation don’t just lead to diabetes—they may also be the missing link behind memory loss and neurodegenerative diseases. The more we understand about how insulin works in the brain, the closer we get to finding new treatments for Alzheimer’s, Parkinson’s, and other brain disorders.
To read more about the specifics about Alzheimer’s disease and insulin resistance click here.
[1]
Akhtar and S. P. Sah, “Insulin signaling pathway and related molecules: Role in neurodegeneration and Alzheimer’s disease,” Neurochemistry International, vol. 135, p. 104707, May 2020, doi: 10.1016/j.neuint.2020.104707.
[2]
Safieh, A. D. Korczyn, and D. M. Michaelson, “ApoE4: an emerging therapeutic target for Alzheimer’s disease,” BMC Med, vol. 17, no. 1, p. 64, Dec. 2019, doi: 10.1186/s12916-019-1299-4.
[3]
What do we know about diet and prevention of alzheimer’s disease? | National Institute on Aging, https://www.nia.nih.gov/health/alzheimers-and-dementia/what-do-we-know-about-diet-and-prevention-alzheimers-disease (accessed Feb. 2025).
[4]
Preventing alzheimer’s disease: What do we know? | National Institute on Aging, https://www.nia.nih.gov/health/alzheimers-and-dementia/preventing-alzheimers-disease-what-do-we-know (accessed Feb. 2025).
Did you know that Alzheimer’s disease (AD) might have more in common with diabetes than we ever imagined? Scientists have discovered a powerful link between insulin resistance – the same problem at the heart of Type 2 Diabetes – and the brain changes seen in Alzheimer’s. Some even call AD “Type 3 Diabetes” because of how insulin dysfunction contributes to memory loss and cognitive decline. But how does this work? And could diabetes medications help fight Alzheimers? [1]
Figure 1 [2]
Insulin: More Than Just a Blood Sugar Regulator
We usually think of insulin as the hormone that controls blood sugar, but it also plays a vital role in the brain. Insulin helps neurons communicate, protects them from damage, and keeps brain cells energized. When everything is working well, insulin binds to receptors on brain cells, triggering pathways that support learning and memory.
Figure 2 [3]: Artstract by Ella Alsleben. Diagram illustrating how insulin signaling through IRS, PI3K, and GSK3 beta interacts with neuroinflammation and oxidative stress pathways – via molecules like caspsases, NFkB, and Nrf2 – to contribute to neurodegeneration and Alzheimer’s disease.
But when insulin signaling is disrupted – known as brain insulin resistance – neurons can’t absorb glucose efficiently, leading to energy shortages, inflammation, and cell damage. This makes it harder for the brain to function, setting the stage for Alzheimer’s. [4]
The Early Warning Signs: Insulin Resistance in the Brain
Long before severe memory loss kicks in, brain insulin resistance begins to take hold – especially in areas critical for memory, like the hippocampus and cortex. Here’s what happens:
Neurons stop responding to insulin: Key signaling pathways that keep brain cells alive and functioning begin to break down.
Glucose metabolism slows down: Brain scans show that memory-related areas start using less glucose, making it harder to form new memories.
Inflammation and oxidative stress rise: Harmful molecules like TNF-a and IL-6 flood the brain, damaging neurons and worsening insulin resistance.
Adding to the problem, amyloid-beta oligomers – toxic protein clumps linked to AD – can actually cause insulin resistance in neurons. This creates a vicious cycle: insulin dysfunction fuels Alzheimer’s, and Alzheimer’s worsens insulin resistance. [5]
Figure 3 [6]
As Alzheimer’s Progresses: Insulin Dysfunction Gets Worse
As the disease advances, insulin resistance in the brain becomes severe:
Insulin receptors break down: The brain can’t properly respond to insulin, leading to widespread metabolic failure.
Neurons lose their survival signals: Key pathways, like P13K/Akt, that protect against cell death become disrupted.
Brain cells starve: Glucose metabolism crashes, leaving neurons without the energy they need to survive.
Amyloid plaques and tau tangles grow: These toxic proteins further block insulin signaling, accelerating brain cell death. [7]
Diabetes and Alzheimer’s: A Dangerous Connection
People with Type 2 Diabetes Mellitus (T2DM) are at a higher risk of developing Alzheimer’s – likely because both conditions involve insulin resistance and chronic inflammation. Research suggests that high insulin levels in the body can actually reduce insulin transport into the brain, making the problem worse.
Figure 4 [8]
Can Diabetes Drugs Help Treat Alzheimer’s?
Metformin: A common diabetes drug that may improve insulin sensitivity and reduce tau protein buildup in the brain.
Intranasal Insulin: Direct delivery of insulin to the brain (through the nose) has shown improvements in memory and cognitive function.
While research on insulin-based Alzheimer’s treatments is ongoing, one thing is clear: managing blood sugar and insulin levels is crucial for brain health.
Here are some lifestyle tips to help reduce your risk:
Eat a balanced diet rich in Whole Foods, healthy fats, and fiber.
Exercise regularly to improve insulin sensitivity.
Get quality sleep – poor sleep can worsen insulin resistance.
Manage stress, as chronic stress affects insulin function.
Figure 5 [9]
Alzheimer’s disease is still a mystery in many ways, but understanding the insulin connection opens up new treatment possibilities. As science continues to evolve, one thing remains certain: taking care of your metabolic health is one of the best things you can do for your brain!
References
[1] de la Monte, S. M., & Wands, J. R. (2008). Alzheimer’s disease is type 3 diabetes—evidence reviewed. Journal of Diabetes Science and Technology, 2(6), 1101–1113. https://doi.org/10.1177/193229680800200619
[2] Man measuring blood sugar pictures, images and stock photos. iStock. (n.d.). https://www.istockphoto.com/photos/man-measuring-blood-sugar
[3] Artstract by Ella Alsleben
[4]Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707
[5] Arnold, S. E., Arvanitakis, Z., Macauley-Rambach, S. L., Koenig, A. M., Wang, H.-Y., Ahima, R. S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L. E., Holtzman, D. M., & Nathan, D. M. (2018). Brain insulin resistance in type 2 diabetes and alzheimer disease: Concepts and conundrums. Nature Reviews Neurology, 14(3), 168–181. https://doi.org/10.1038/nrneurol.2017.185
[6] Zimy. (2024, April 2). Insulin and alzheimer’s disease. Cobbers on the Brain. https://blog.cord.edu/cobbersonthebrain/2024/04/02/insulin-and-alzheimers-disease/
[7] Akhtar, A., & Sah, S. P. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and alzheimer’s disease. Neurochemistry International, 135, 104707. https://doi.org/10.1016/j.neuint.2020.104707
[8] Movassat, J., Delangre, E., Liu, J., Gu, Y., & Janel, N. (2019, June 3). Hypothesis and theory: Circulating alzheimer’s-related biomarkers in type 2 diabetes. insight from the goto-kakizaki rat. Frontiers. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2019.00649/full
[9] Sarkar, N. (n.d.). Embrace healthy lifestyle, take balanced diet, exercise, sleep, stress relief, no smoking. Vecteezy. https://www.vecteezy.com/vector-art/46149206-embrace-healthy-lifestyle-take-balanced-diet-exercise-sleep-stress-relief-no-smoking
The Domino Effect: Alzheimer’s disease follows a pathogenesis that includes a cascade of inflammation, synaptic dysfunction, and hyper-phosphorylation of Tau proteins. P13k is a serine/threonine protein kinase. This is an essential signaling component, especially in an irreversible neurodegenerative disease like Alzheimer’s.
(STK) serine/threonine kinase is responsible for cellular processing; within P13k, there is a catalytic subunit and a regulatory subunit. I like to think of the two as a relationship, similar to an employee and a manager. The catalytic subunit is an active site for phosphorylation and, in turn, enzymatically catalyzes a reaction. As the catalytic subunit respondsto the regulatory subunit, the manager, its job is to facilitate, control, or inhibit these reactions.
P13K: The Trigger
P13K is an enzyme that grows cells and initiates cell communication by transmitting signals. It is a critical for synaptic health.
As P13k’s job is regulation, it can become uncontrolled or abnormal and, in turn, the body responds in vicious ways as the P13k pathway is principle in human disease
The P13k/Akt pathway combustion accelerates neurodegeneration which triggers this cascade of events.
Akt Activation
Aktactivation is triggered by various cellular components involved in Alzheimer’s disease,stems primarily from Amyloid–B and Neurofibrillary tangles, which are neurodegenerative proteins found in patients with Alzheimer’s.
The activation ofPI3K facilitates Akt.
Serine/Threonine protein hasa catalytic domain and a regulatory domain,involvedin PI3K/Akt pathways and phosphoinositide.
Phosphoinositide-dependent protein kinase-1 (PDK1) is responsible for the phosphorylation of Akt,whichhas three subtypes:Akt1,Akt2,andAkt3.
GSk-3B propagates apoptotic signals and facilitates degradation.
This, however, creates inactivation of GSk-3B.. which in turn accelerates Tau protein phosphorylation.
Tau Proteins
Tau proteins are the main component of neurofibrillary tangles, which is the abnormal protein that promotes Alzheimer’s disease.
Inactivation of GSK-3B causes the hyper-phosphorylation of Tau proteins.
The hyper-phosphorylation of Tau proteins drives disease development.
Tau proteins are essentially responsible for axonal transport and neurite growth, so when Tau becomes hyper-phosphorylated ,it cannot attach regularly to microtubules.
Therefore, neurofibrillary tangles are formed, which affect cell communication and plasticity between neurons.
Figure1: Comparing P13K pathway in normal functioning via P13k in Alzheimers Disease
Alzheimers disease & P13K
P13K Pathway is critical in a signaling cascade which develops apoptosis and neurodegeneration,
Creates extracellular Amyloid- B plaques which are formed by amyloid cursor protein
Creates intracellular neurofibrillary tangles occurring from hyper-phosphorylated Tau proteins.
Amyloid-B and Neurofibrillary tangles are pathological marks that indicate Alzheimers disease.
In relation to therapeutic research, insulin signaling has been used as a neuromodulator to create ‘brain insulin resistance.’ which stemmed from the idea that dysfunctional insulin signaling was contributing to the symptomatology of Alzheimer’s disease.
Dementia is a pathological disease, as Alzheimer’s follows the P13k/Akt pathway it produces hallmarks of AD, therefore, generates dysregulated brain insulin signaling.
Footnotes:
Povala, G., Bastiani, M. A. D., Bellaver, B., Ferreira, P. C. L., Ferrari-Souza, J. P., Lussier, F. Z., Souza, D. O., Rosa-Neto, P., Zatt, B., Pascoal, T. A., Zimmer, E. R., & Initiative, the A. D. N. (2022, January 1). Serine/threonine kinase activity associates with brain glucose metabolism changes in alzheimer’s disease. medRxiv. https://www.medrxiv.org/content/10.1101/2022.10.31.22281751v1.full
Razani, E., Pourbagheri-Sigaroodi, A., Safaroghli-Azar, A., Zoghi, A., Shanaki-Bavarsad, M., & Bashash, D. (2021, November). The PI3K/akt signaling axis in alzheimer’s disease: A valuable target to stimulate or suppress? Cell stress & chaperones. https://pmc.ncbi.nlm.nih.gov/articles/PMC8578535/
Rosenberger, A. F. N., Hilhorst, R., Coart, E., García Barrado, L., Naji, F., Rozemuller, A. J. M., van der Flier, W. M., Scheltens, P., Hoozemans, J. J. M., & van der Vies, S. M. (2016). Protein kinase activity decreases with higher braak stages of alzheimer’s disease pathology. Journal of Alzheimer’s disease : JAD. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927853/
SP;, A. A. (2020). Insulin signaling pathway and related molecules: Role in neurodegeneration and alzheimer’s disease. Neurochemistry international. https://pubmed.ncbi.nlm.nih.gov/32092326/
Taylor, H. B. C., & Jeans, A. F. (2021, August 31). Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau. Cell Reports. https://www.sciencedirect.com/science/article/pii/S2211124721010810
[1]
[5]
