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

1. 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.
2. 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.
3. 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:

1. 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]

2. 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).

3. 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.

4. Reduce Stress and Inflammation

• Chronic stress increases cortisol, which contributes to brain damage.
• Practice meditation, yoga, or deep breathing to reduce stress hormones.

5. 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]

6. 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]

10. 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]

10. 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).

[5]

“Alzheimer’s disease: Causes, stages, Symptoms & Prevention,” Drugwatch.com, https://www.drugwatch.com/health/alzheimers-disease/ (accessed Feb. 2025).

Figure 1

Every year, an estimated 3.8 million concussions [1] occur in the U.S. alone, with many going undiagnosed. While these injuries may seem minor, new research suggests that even a single concussion can trigger long-lasting brain damage.

Concussions don’t just disrupt the brain; they set off a chain reaction of cellular and metabolic disruptions. This includes impaired energy production, protein accumulation, and chronic neurodegeneration. And when the brain experiences multiple concussions before fully recovering, the damage can become even more severe, increasing the risk of long-term cognitive impairment, Alzheimer’s disease, and Chronic Traumatic Encephalopathy (CTE).  [2]

Therefore, understanding the long-term effects of concussions is critical, not just for athletes, but for anyone who may suffer a head injury.

The Brain’s First Responders: Microglia and Astrocytes in Inflammation

The brain is a highly protected organ, yet it is not immune to injury. When trauma occurs, the body’s immune system cannot send white blood cells past the blood-brain barrier. Instead, the brain relies on its own immune defense: microglia and astrocytes. These glial cells work to protect neurons, but their response to injury is sometimes not as favorable.

Initially, glial cells act as first responders, helping to contain damage. But if their activation is prolonged, they can contribute to chronic inflammation, leading to long-term neurological problems. Therefore, understanding how microglia and astrocytes function, and how we might regulate their response could be the key to developing new treatments for brain injuries.

  Figure 2

Microglia: The Immune Warriors

Microglia are the brain’s resident immune cells, constantly monitoring their environment for damage or infection. When they detect a threat, they activate and shift into a pro-inflammatory (M1) state, releasing molecules as shown in figure 3 such as: [3]

• Tumor necrosis factor-alpha (TNF-α)
• Interleukin-1 beta (IL-1β)
• Interleukin-6 (IL-6)

These inflammatory signals help clear debris and protect against infections, but if microglia remain overactive, they can contribute to prolonged inflammation, damaging healthy brain cells. As seen in Figure 3, prolonged inflammation in the brain can contribute to neurodegenerative diseases like Alzheimer’s and chronic traumatic encephalopathy  (CTE).[6]

After a mild traumatic brain injury (mTBI), microglia are the first to respond. They rush to the site of injury and release these inflammatory molecules to clean up damage and protect the brain. However, sometimes they don’t shut off when they should, leading to long-lasting inflammation that can cause memory problems, mood changes, and increase the risk of future brain damage.

To heal properly, microglia need to switch into a repair mode (M2 state), where they release anti-inflammatory molecules like:

• Interleukin-10 (IL-10)
• Transforming growth factor-beta (TGF-β)

In this state, microglia help repair tissues and restore homeostasis.

Figure 3

Astrocytes: The Brain’s Support Network

While microglia act as the brain’s immune soldiers, astrocytes are more like engineers, they provide structure, support, and help keep the brain’s environment balanced. But after a brain injury, astrocytes change their behavior in a process called reactive astrogliosis . [4]  This response helps protect the brain, but if it goes too far, it can cause problems.

When astrocytes become reactive, they:

• Produce more glial fibrillary acidic protein (GFAP) – This helps form a protective barrier around injured areas, but too much can block nerve regrowth, making recovery harder.
• Release inflammatory molecules (IL-1β, IL-6, MCP-1) – These signals attract more immune cells to the injury site, which can be helpful at first but may also prolong inflammation and damage healthy tissue.
• Control neurotransmitters like glutamate – Normally, astrocytes remove excess glutamate to keep brain activity in balance. But after an injury, they can struggle to regulate it, leading to excitotoxicity, where too much glutamate overstimulates and kills neurons. [5]

Astrocytes and the Blood-Brain Barrier: The Brain’s Gatekeepers

In addition to supporting neurons and regulating inflammation, astrocytes play a key role in maintaining the blood-brain barrier (BBB), a protective shield that controls what enters and exits the brain. The BBB prevents harmful substances like toxins, bacteria, and inflammatory molecules from reaching brain tissue, while allowing essential nutrients to pass through. Astrocytes strengthen this barrier by releasing signals that help maintain its integrity.

After an mTBI (mild traumatic brain injury), astrocytes react to the damage, but this can have both helpful and harmful effects:
✅ Protective role – Astrocytes reinforce the BBB to prevent further injury and infection.
❌ Barrier breakdown – If inflammation is prolonged, astrocytes may fail to maintain the BBB, allowing harmful substances to enter the brain.

   Figure 4

Potential Treatments for mTBI Recovery

Because both microglia and astrocytes play dual roles in brain inflammation—acting as both protectors and potential sources of harm—scientists are exploring treatments aimed at modulating their responses. Potential therapies include:

• Microglia-targeted therapies: Encouraging microglia to shift from an M1 inflammatory state to an M2 repair-focused state. Minocycline, an anti-inflammatory antibiotic, shows promise in reducing prolonged inflammation [7]
• Astrocyte regulation: Enhancing astrocyte function may improve glutamate clearance, reducing excitotoxicity and promoting neuronal survival. Certain drugs and omega-3 fatty acids may support this function.

A concussion isn’t just a quick shake it off moment; it’s your brain literally hitting the brakes and scrambling to recover. Microglia and astrocytes rush in like a cleanup crew, but if they overstay their welcome, they can cause more harm than good, leading to long-term brain issues.

So, give your brain the time it needs to heal. Rest, recover, and don’t rush back into action too soon. Pushing through too early can make things worse, but proper care can set you up for a stronger, healthier comeback. Your brain does a lot for you, make sure you take care of it, too!

Figure 5

Footnotes

[1] Hallock, H., Mantwill, M., Vajkoczy, P., Wolfarth, B., Reinsberger, C., Lampit, A., & Finke, C. (2023). Sport-Related Concussion: A Cognitive Perspective. Neurology. Clinical practice, 13(2), e200123. https://doi.org/10.1212/CPJ.0000000000200123

[2] Matthews,(2017). What is Chronic Traumatic Encephalopathy? | Saponara Brain & Spine Center. Www.saponara.com. https://www.saponara.com/what-is-chronic-traumatic-encephalopathy/

[3] Colonna, M., & Butovsky, O. (2017). Microglia Function in the Central Nervous System During Health and Neurodegeneration. Annual review of immunology, 35, 441–468. https://doi.org/10.1146/annurev-immunol-051116-052358

[4]‌ Matusova, Z., Hol, E. M., Pekny, M., Kubista, M., & Valihrach, L. (2023). Reactive astrogliosis in the era of single-cell transcriptomics. Frontiers in cellular neuroscience, 17, 1173200. https://doi.org/10.3389/fncel.2023.1173200

[5] Michinaga, S., & Koyama, Y. (2021). Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury. International Journal of Molecular Sciences, 22(12), 6418. https://doi.org/10.3390/ijms22126418

[6] Postolache, T. T., Wadhawan, A., Can, A., Lowry, C. A., Woodbury, M., Makkar, H., Hoisington, A. J., Scott, A. J., Potocki, E., Benros, M. E., & Stiller, J. W. (2020). Inflammation in Traumatic Brain Injury. Journal of Alzheimer’s disease : JAD, 74(1), 1–28. https://doi.org/10.3233/JAD-191150

[7] Scott, M. C., Bedi, S. S., Olson, S. D., Sears, C. M., & Cox, C. S. (2021). Microglia as therapeutic targets after neurological injury: strategy for cell therapy. Expert opinion on therapeutic targets, 25(5), 365–380. https://doi.org/10.1080/14728222.2021.1934447

Introduction

Diffuse Axonal Injury (DAI) and Traumatic Axonal Injury (TAI) are serious brain injuries caused by traumatic events, such as concussions, car accidents, and falls. These lesions primarily impact the brain’s white matter, resulting in serious neurological deficits. This article dives into the fundamental principles that underpin these injuries, their clinical ramifications, and continuing research to improve diagnosis and therapy.

Summary of the Science

DAI and TAI develop as a result of shearing pressures applied to the brain during fast acceleration and deceleration, causing widespread damage to axons—the long fibers that connect neurons and promote communication within the brain.

Pathophysiology

1. Initial Mechanical Damage:

• Upon impact, the brain undergoes rapid movement inside the skull, causing stretching and tearing of axons.
• Mechanoporation, or the disruption of cell membranes, results in ionic imbalances, triggering a cascade of metabolic disturbances

2. Neurometabolic Cascade:

• The injury leads to the indiscriminate release of glutamate, a neurotransmitter that contributes to excitotoxicity.
• There is a subsequent increase in intracellular calcium, which impairs mitochondrial function and energy production (Figure 1).
• An energy crisis ensues as ATP-dependent ion pumps work to restore homeostasis, leading to a temporary state of metabolic dysfunction.

3. Axonal Dysfunction and Disconnection:

Cytoskeletal proteins such as neurofilaments collapse, leading to axonal swelling and, in severe cases, disconnection.

Amyloid precursor protein (APP) accumulation at damaged sites is a hallmark of axonal injury, often detected via advanced imaging techniques like Diffusion Tensor Imaging (DTI) (Figure 2).

2.Secondary Injury Processes:

Inflammatory responses contribute to delayed cell death and chronic white matter degeneration.

Repeated injuries, especially within a vulnerable period, exacerbate neurodegeneration and long-term cognitive decline.

Clinical Implications

Patients with DAI or TAI present with a spectrum of symptoms depending on the severity of the injury. Common clinical manifestations include:

• Mild cases include headaches, dizziness, memory problems, and impaired cognitive processing.
• Moderate to severe cases include loss of consciousness, a lengthy coma, and considerable motor or cognitive impairment.

The susceptibility period following a first injury raises the chance of recurrent trauma, resulting in worse consequences. According to studies, metabolic recovery in humans might take weeks to months, needing ongoing monitoring before resuming to high-risk activities.

Advances in Diagnostics and Imaging

• Diffusion Tensor Imaging (DTI) improves the detection of white matter alterations by tracking the flow of water molecules along axonal tracts.
• Magnetic resonance spectroscopy (MRS) detects metabolic abnormalities, such as decreased N-acetylaspartate (NAA) levels, which are symptomatic of neuronal injury.
• Biomarker research involves investigating blood-based indicators such as tau proteins and neurofilament light chains (NfL) for early diagnosis and prognosis.

Future Directions and Treatment Options

• Neuroprotective Strategies: Therapies that address excitotoxicity, oxidative stress, and inflammation are being investigated.
• Rehabilitation and Cognitive treatment: Individualized rehabilitation regimens that include physical treatment, cognitive exercises, and lifestyle changes aid in functional recovery.
• Preventive Measures: New helmet designs and updated concussion protocols aim to reduce the impact of recurrent head trauma in contact sports and high-risk occupations.

Conclusion

Diffuse Axonal Injury and Traumatic Axonal Injury are severe types of traumatic brain injury with intricate underlying mechanisms. Advances in neuroimaging, biomarker studies, and targeted medicines offer hope for improved diagnosis and treatment of many disorders. Continued research is required to discover effective treatments and improve the results for afflicted people.

References

Giza, C. C., & Hovda, D. A. (2014). The new neurometabolic cascade of concussion. Neurosurgery, 75(S4), S24-S33.

Vagnozzi, R., et al. (2010). Assessment of metabolic brain damage and recovery following mild traumatic brain injury. Brain, 133(11), 3232-3242.

Johnson, V. E., Stewart, W., & Smith, D. H. (2013). Axonal pathology in traumatic brain injury. Experimental Neurology, 246, 35-43.