High Mobility Group Box 1 (HMGB1) in Vascular Dementia: Mechanism, Biomarker Potential, and Therapeutic Implication

Vascular dementia (VaD) is a prevalent neurodegenerative disorder characterized by cognitive impairment resulting from cerebrovascular pathology. While several mechanisms contribute to the pathogenesis of VaD, the role of neuroinflammation has gained increasing attention. High Mobility Group Box 1 (HMGB1), a multifunctional protein associated with inflammation and cell damage, has emerged as a potential key player in VaD. This comprehensive research explores the multifaceted role of HMGB1 in VaD, encompassing its underlying mechanisms, biomarker potential, and therapeutic implications.

VaD is the second most common cause of dementia, following Alzheimer's disease (AD)1,2. Cerebrovascular pathology, including ischemic events and small vessel disease, contributes significantly to VaD development2,3. Neuroinflammation is increasingly recognized as a critical factor in VaD progression3,4. HMGB1, initially identified as a nuclear protein, has been implicated in various inflammatory and neurodegenerative processes, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, traumatic brain injury, and cerebrovascular disease5.

HMGB1 is a nuclear protein that can be actively secreted or passively released by various cell types during inflammation, stress, or injury5. In the context of vascular dementia (VaD), the role of HMGB1 has been a subject of research, although it's important to note that the exact mechanisms are still being elucidated. Here are some of the ways in which HMGB1 is believed to be involved in the pathophysiology of VaD:


  1. Neuroinflammation: HMGB1 is known to act as a proinflammatory cytokine when released into the extracellular space6. In VaD, chronic cerebral hypoperfusion and vascular damage can trigger inflammation7. HMGB1 may contribute to this process by promoting the release of other inflammatory molecules and the activation of microglia and astrocytes5,7.
  2. Blood-Brain Barrier Disruption: Vascular damage is a hallmark of VaD. HMGB1 has been implicated in blood-brain barrier (BBB) dysfunction. Its release can lead to increased permeability of the BBB, allowing harmful substances to enter the brain more easily8,9. This can exacerbate neuroinflammation and neuronal damage.
  3. Neuronal Damage: HMGB1 may contribute to neuronal damage in VaD. It can induce neurons' apoptosis (programmed cell death), exacerbating cognitive impairment5,7. This effect may be related to the neuroinflammatory response triggered by HMGB1.
  4. Oxidative Stress: HMGB1 has also been associated with oxidative stress10, which plays a role in neurodegenerative conditions, including VaD11. Oxidative stress can lead to cellular damage and contribute to cognitive decline10,11.


Biomarker Potential of HMGB1 for VaD

HMGB1 may serve as a biomarker for VaD. Elevated levels of HMGB1 have been observed in the cerebrospinal fluid of individuals with ischemic stroke12, a risk factor of VaD, suggesting its potential use as a diagnostic or prognostic marker13. The presence of elevated HMGB1 levels may support the clinical diagnosis of VaD and help differentiate it from other types of dementia, such as Alzheimer's disease13. Monitoring HMGB1 over time could provide insights into disease progression and response to treatment in individuals with VaD13,14.


Potential Therapeutic Target of HMGB1 in VaD

Understanding the role of HMGB1 in VaD has led to investigations into therapeutic strategies aimed at blocking its activity. In preclinical studies, blocking HMGB1 has shown promise in reducing cognitive deficits in animal models of various neurological diseases7,13,15. It's important to recognize that HMGB1 has both harmful and beneficial properties, and a successful therapeutic approach would require a delicate balance16. HMGB1 holds potential as a therapeutic target in VaD by modulating its inflammatory and neuroprotective properties16. However, extensive research and clinical trials are needed to determine the safety and efficacy of HMGB1-targeted therapies in the context of VaD.



HMGB1 emerges as a significant player in the pathogenesis of VaD, with potential as both a biomarker and therapeutic target. Further investigations are warranted to harness the full potential of HMGB1 in improving the diagnosis and management of VaD, ultimately enhancing the quality of life for affected individuals.



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