Morning Blue Light Therapy for TBI, Alzheimer’s, and Glymphatic Drainage in ME/CFS and Long Haul
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
Blue Light Therapy
In 2017, an article discussing how morning exposure to blue light (Blue Light Therapy) helps with recovery from traumatic brain injury (TBI) was published. More recently, in 2025 an article came out touting the benefits of morning Blue Light Therapy for Alzheimer’s. I have personal experience with this, as Blue Light Therapy was part of my own healing from two separate brain injuries. Well, it turns out that blue light helps initiate glymphatic drainage. This is important because, in short, the glymphatic drainage system functions to clear metabolic waste from the brain, and dysfunctional glymphatic drainage is a suspected component of Long Haul and ME/CFS and dysregulation of cerebrospinal fluid (CSF).
Aquaporin-4 (AQP4) is a water protein channel in the brain that helps facilitate normal glymphatic drainage. The development of antibodies to AQP4 can be an issue, which is why I test for these antibodies when I suspect a client may have issues with glymphatic drainage. Interestingly, Dr. Steven Gundry, MD espouses that lectins negatively affect Aquaporin-4.
Why Read This Article?
You may be interested in reading this article if:
You want to learn about how Blue Light Therapy can help with TBI recovery.
You want to understand how Blue Light Therapy can help with Alzheimer’s.
You want to understand how Blue Light Therapy impacts glymphatic drainage.
You want to learn about Aquaporin-4’s impact on glymphatic drainage.
Highlights From A Study On Blue Light Therapy and TBI
"We observed a significant impact of the blue light treatment (relative to the placebo) on the amount of water diffusion for multiple brain areas, including the corpus callosum, anterior corona radiata, and thalamus. Moreover, many of these changes were associated with improvements in sleep latency and delayed memory. These findings suggest that blue wavelength light exposure may serve as one of the potential non-pharmacological treatments for facilitating structural and functional recovery following mTBI…." [1]
Highlights From A Study On Blue Light Therapy and Alzheimer’s
“Our findings reveal that light treatment prevents memory decline in 4-month-old 5xFAD mice and motivation loss in 14-month-old 5xFAD mice, accompanied by restoration of glial water channel aquaporin-4 polarity, improved brain drainage efficiency, and a reduction in hippocampal lipid accumulation. We further demonstrate the beneficial effects of 40 hertz blue light are mediated through the activation of the vLGN/IGL-Re visual circuit. Notably, concomitant use of anti-Aβ antibody with 40 hertz blue light demonstrates improved soluble Aβ clearance and cognitive performance in 5xFAD mice. These findings offer functional evidence on the therapeutic effects of 40 hertz blue light in Aβ-related pathologies and suggest its potential as a supplementary strategy……Here, the authors show that 40 hertz blue light activates a visual circuit to boost glymphatic drainage, and enhances memory, motivation, and anti-Aβ therapy efficacy in a mouse model of AD…”[2]
40 Hz blue light treatment improves memory functions in 4-month-old 5xFAD mice
Blue light treatment increases glymphatic drainage in 4-month-old 5xFAD mice
AQP4 polarity, glymphatic drainage efficiency, and cognitive functions of 5xFAD mice are improved by 40 Hz blue light through the activation of vLGN/IGL-Re visual circuit
Blockade of brain drainage pathway or AQP4 function prevents the improvement of memory functions in 5xFAD mice by blue light treatment
Blue light treatment decreases lipid accumulation in the hippocampus of 5xFAD mice
Blue light treatment enhances motivative behaviors and glymphatic drainage in 14-month-old 5xFAD mice
Blue light treatment enhances the efficacy of anti-Aβ immunotherapy on cognitive improvement and soluble Aβ reduction
“To summarize, our findings reveal that low-intensity 40 Hz blue light treatment enhances glymphatic drainage and cognitive performance that are functionally associated with the vLGN/IGL-Re circuit and AQP4. The same treatment also improves motivation and glymphatic function in the middle age 5xFAD mice. Furthermore, the combination of anti-Aβ immunotherapy with 40 Hz blue light treatment exhibits increased effects than immunotherapy alone in alleviating cognitive impairment and reducing soluble Aβ42. Collectively, our findings highlight the therapeutic potential and safety of low-intensity 40 Hz blue light treatment and as the adjunctive therapy of anti-Aβ immunotherapy for patients with dementia.”[2]
Glymphatic Drainage and the Role of Aquaporin-4
Glymphatic drainage refers to the removal of metabolic waste products from the brain via the glymphatic system.
Glymphatic System:
The glymphatic system is a brain-wide pathway that supports the exchange of CSF and interstitial fluid (ISF) in the brain. It plays a vital role in removing waste products, such as amyloid-beta, from the brain.
“The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular end feet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport.”[4]
Aquaporin-4 (AQP4):
AQP4 is essential for rapid glymphatic transport, particularly in facilitating the movement of water between the perivascular space and the glial tissue. It's also involved in regulating water balance in the brain.
Aquaporin-4 (AQP4) is a crucial protein in the brain's glymphatic system, which is responsible for removing waste products and clearing fluid from the brain. It acts as a water channel, facilitating the exchange of fluid between the brain and the cerebrospinal fluid (CSF). AQP4 is primarily found on the astrocytes in the perivascular spaces, the area around blood vessels in the brain.
“The clearance function is essential for maintaining brain tissue homeostasis, and the glymphatic system is the main pathway for removing brain interstitial solutes. Aquaporin-4 (AQP4) is the most abundantly expressed aquaporin in the central nervous system (CNS) and is an integral component of the glymphatic system. In recent years, many studies have shown that AQP4 affects the morbidity and recovery process of CNS disorders through the glymphatic system, and AQP4 shows notable variability in CNS disorders and is part of the pathogenesis of these diseases. Therefore, there has been considerable interest in AQP4 as a potential and promising target for regulating and improving neurological impairment. This review aims to summarize the pathophysiological role that AQP4 plays in several CNS disorders by affecting the clearance function of the glymphatic system. The findings can contribute to a better understanding of the self-regulatory functions in CNS disorders that AQP4 were involved in and provide new therapeutic alternatives for incurable debilitating neurodegenerative disorders of CNS in the future.”[3]
Location and Importance:
AQP4 is highly concentrated in the perivascular endfeet of astrocytes, where it's critical for maintaining brain homeostasis. It's the most abundant aquaporin in the central nervous system (CNS).
Consequences of APQ4 Dysfunction:
Disrupted AQP4 expression or localization can lead to glymphatic system dysfunction, potentially causing waste product accumulation and contributing to neurodegenerative diseases like Alzheimer's disease.
Implications for Neurodegenerative Diseases:
Studies have shown that AQP4 levels in CSF are higher in individuals with neurodegenerative diseases, suggesting a potential link between AQP4 and the progression of these conditions.
In essence, AQP4 acts as a gatekeeper for water movement in the glymphatic system, playing a crucial role in brain waste clearance and fluid balance. Its dysfunction can have significant implications for brain health and neurodegenerative diseases.
Causes of Blockade of AquaPorin-4 [5]
Aquaporin-4 (AQP4) blockade can be caused by various factors, including genetic mutations, autoimmune responses, and cellular signaling pathways. Blockade can also be induced by certain drugs and cellular stress.
Here's a more detailed breakdown:
Mutations in the AQP4 gene can impair its water permeability, potentially leading to a functional block. [6]
Autoimmune Responses (Rare):
In Neuromyelitis Optica Spectrum Disorder (NMOSD), anti-AQP4 antibodies attack and damage the central nervous system, leading to inflammation and AQP4 dysfunction. [7,8]
Cellular Signaling:
Phosphorylation of AQP4 at specific sites, like Ser180, can lead to its inhibition, while phosphorylation at other sites, like Ser111, can activate it. [9]
Calmodulin Interaction:
Calmodulin directly binds to the carboxyl terminus of AQP4, influencing its localization and potentially causing a conformational change that affects water transport. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies. [10]
Inhibition of AQP4 can alter the osmotic stress in the extracellular space surrounding microglia, potentially leading to their activation and inflammation. However, the mechanism behind the decrease of the AQP4 and activation of microglia is less obvious and still unknown. One possible mechanism behind the changes observed in post-traumatic or ischemic microglia activation and cytokine release in response to AQP4 downregulation or inhibition may be partly due to the presence of stretch-activated Cl- channels expressed in microglia. Stretch-activated/swelling-activated Cl- channels are activated by osmotic stress. It has been observed that the activation of these channels contributes the maintenance of the non-activated (ramified) phenotype of microglia . Because AQP4 is responsible for water transport, inhibition of AQP4 either through genetic deletion or siRNA will alter the osmotic stress within the extracellular space surrounding the microglia, changing the activation status of the swelling activated chloride channels, resulting in microglial activation. Another possibility lies in the cross-talk that occurs between astrogliosis and microglial activation. It is possible that the decreased extent of injury-induced reactive astrogliosis as a result of knocking down AQP4 caused increased microglial activity. [11]
IL-1β Stimulation:
IL-1β, a pro-inflammatory cytokine, can induce AQP4 expression in astrocytes, but blocking IL-1β can decrease AQP4-related edema. Elevated levels of IL-10, TNF-α, IL-1β, and IL-2 are found after middle cerebral artery occlusion in the rat brain. An increase in TNF-α, IL-6, and IL-1β is found after transient cerebral ischemia. The surge of inflammatory cytokines in the brain can be detected within an hour after injury. In astrocytes, IL-1β is a potent activator of NFκB, which leads to increased AQP4 transcription. Ito et al. confirmed that IL-1β was a potent inducer of AQP4 expression in astrocytes and that this induction was mediated by NF-κB activation. Another cytokine, TNF-α, is also a potent activator of NFκB . Interestingly, TNF-α seems to interact with IL-1 in a positive-feedback system to induce the spread of inflammation. This positive feedback loop can cause a sustained elevation of cytokines. The up-regulation of AQP4 by TNF-α has been confirmed in an epithelial cell line . In addition, VEGF has been found to induce up-regulation of Aqp4 mRNA in vivo. VEGF promotes angiogenesis and increases vascular permeability in the brain, and its transcript starts to increase as early as 2 hours after ischemic injury. Like the opposing effects of AQP4 in different edematous phases post-injury, VEGF injection has a detrimental role if injected 1 hour after injury, but promotes recovery when injected 48 hours after injury. We conjecture that the sustained rise of AQP4 levels observed in brain pathologies is mainly caused by the elevation of cytokines during neuroinflammation. [12]
Certain anti-epileptic drugs, like topiramate, have been reported to block AQP4 function.
Conditions like traumatic brain injury, stroke, and ischemia can disrupt AQP4 function and localization.
Sleep disruption can affect the glymphatic system, a pathway involving AQP4 in brain waste clearance, and impairing this function. Recently, we have demonstrated that AQP4 localization is also dynamically regulated at the subcellular level, affecting membrane water permeability. Ageing, cerebrovascular disease, traumatic CNS injury, and sleep disruption are established and emerging risk factors in developing neurodegeneration, and in animal models of each, impairment of glymphatic function is associated with changes in perivascular AQP4 localization. CNS oedema is caused by passive water influx through AQP4 in response to osmotic imbalances. We have demonstrated that reducing dynamic relocalization of AQP4 to the BSCB/BBB reduces CNS oedema and accelerates functional recovery in rodent models. Given the difficulties in developing pore-blocking AQP4 inhibitors, targeting AQP4 subcellular localization opens up new treatment avenues for CNS oedema, neurovascular and neurodegenerative diseases, and provides a framework to address fundamental questions about water homeostasis in health and disease. [14]
Changes in mitochondrial function at astrocyte end-feet can affect AQP4 expression and water transport. The increase in pathological mitochondria at the astrocyte end-feet and the decrease in normal mitochondria will inevitably lead to the dysfunction of water and substance exchange, which may also be one of the mechanisms for the decreased expression of perivascular AQP4. [15]
Circulating IgG1 antibodies against AQP4 are a hallmark of Neuromyelitis Optica (NMO).
Summary
Blue Light Therapy may be something to consider in cases where glymphatic drainage issues are suspected or confirmed through testing. Testing via Vibrant America can provide additional information related to Aquaporin-4. Although the Alzheimer’s testing to date is on mice, the results certainly look interesting. Blue light devices are readily available and inexpensive.
References:
[1] “Blue-Light Therapy following Mild Traumatic Brain Injury: Effects on White Matter Water Diffusion in the Brain”, By Baja, et. al., Frontiers In Neurology, 21 November 2017. Section Neurotrauma. Volume 8 - 2017 | https://doi.org/10.3389/fneur.2017.00616[2] “Modulation of glymphatic system by visual circuit activation alleviates memory impairment and apathy in a mouse model of Alzheimer’s disease”, By Wu, et. al. Nature Communications, . 2025 Jan 2;16:63. doi:10.1038/s41467-024-55678-w[3] “Aquaporin-4 in glymphatic system, and its implication for central nervous system disorders”, By Peng, et. al. Neurobiol Dis. 2023 Apr:179:106035. doi: 10.1016/j.nbd.2023.106035.Epub 2023 Feb 15.[4] “Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation”, By Gomolka, et. al. eLife . 2023 Feb 9;12:e82232. doi:10.7554/eLife.82232. PMCID: PMC9995113 PMID: 36757363[5] Mechanisms Underlying Aquaporin-4 Subcellular Mislocalization in Epilepsy, By Szu, et. al. Front Cell Neurosci . 2022 Jun 6;16:900588. doi: 10.3389/fncel.2022.900588[6] D184E mutation in aquaporin-4 gene impairs water permeability and links to deafness, by Nichia, et. al. Neuroscience . 2011 Dec 1:197:80-8. doi: 10.1016/j.neuroscience.2011.09.023. Epub 2011 Sep 16. PMID: 21952128. DOI: 10.1016/j.neuroscience.2011.09.023[7] Signs, symptoms, and damage of NMOSD | Navigating NMOSD[8] Eculizumab in Aquaporin-4–Positive Neuromyelitis Optica Spectrum Disorder, By Pitock, et. al. The New England Journal of Medicine. Published May 2, 2019N Engl J Med 2019;381:614-625. DOI: 10.1056/NEJMoa1900866. VOL. 381 NO. 7[9] Physiological Roles of Aquaporin-4 in Brain, By Erlend A. Nagelhus and Ole P. Ottersen. Physiological Reviews. 01 Oct 2013https://doi.org/10.1152/physrev.00011.2013[10] Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema, By Kitchen, et. al. Cell, Volume 181, Issue 4p784-799.e19May 14, 2020 . [11] Aquaporin 4: a player in cerebral edema and neuroinflammation, By Andrew M Fukuda J Neuroinflammation . 2012 Dec 27;9:279. doi: 10.1186/1742-2094-9-279. PMCID: PMC3552817 PMID: 23270503[12] Dynamic regulation of aquaporin-4 water channels in neurological disorders, By Hsu, et. al. Croat Med J . 2015 Oct;56(5):401–421. doi: 10.3325/cmj.2015.56.401. PMCID: PMC4655926 PMID: 26526878[13] Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease, By Mader, et. al. Cells . 2019 Jan 27;8(2):90. doi: 10.3390/cells8020090. PMCID: PMC6406241 PMID: 30691235[14] Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis , By Mootaz M Salman , et. al. Brain, Volume 145, Issue 1, January 2022, Pages 64–75, https://doi.org/10.1093/brain/awab311[15] Aquaporin-4 and Cognitive Disorders, By Wang, et. al. Aging Dis . 2022 Feb 1;13(1):61–72. doi: 10.14336/AD.2021.0731. PMCID: PMC8782559 PMID: 35111362