Understanding the role of oxidative stress in the pathogenesis of Alzheimer's disease

The number of people suffering from Alzheimer's disease (AD) may reach 100 million by 2050, but no effective treatment has yet been found for this disease. Leading researchers from around the world assessed how oxidative stress (OS) may cause AD and reviewed potential therapeutic targets and neuroprotective drugs to combat the disease in a collection of papers in a special issue of the Journal of Alzheimer's Disease, published by IOS Press.

Characteristics of Alzheimer's disease

Alzheimer's disease is the most common form of dementia, affecting the areas of the brain responsible for thinking, memory and language. It is the leading cause of disability in people over 65 years of age and is one of the top 10 leading causes of death in the United States. AD is characterized by abnormal deposition of amyloid beta peptide and intracellular accumulation of neurofibrillary tangles of hyperphosphorylated tau protein. Although the diagnosis of AD has improved significantly, the exact cause of the disease has not yet been identified. Key objectives include investigating factors beyond the two dominant hypotheses—amyloid beta deposition and tau protein phosphorylation.

Oxidative stress hypothesis

It has been suggested that other factors may cause the disease, and one of them is OS, a process associated with an imbalance between antioxidants and oxidants. The OS hypothesis suggests that the brain remains multifunctional as long as "free radicals" generated by various biochemical reactions in the brain are neutralized by antioxidants.

Special issue editor Pravat K. Mandal, Ph.D., scientist and former director of the National Center for Brain Research in Gurgaon, India, and professor emeritus at the Florey Institute of Neuroscience and Mental Health in Melbourne, Australia, explains: “The OS hypothesis has been advanced for more than a quarter centuries ago. Recently, researchers have shown renewed interest in studying the potential benefits of OC neutralization, which has led to the development of numerous studies to test its effects. As long as there is a balance between pro-oxidant molecules and antioxidants, the brain remains multifunctional and healthy. Although there are several such antioxidants, glutathione has received significant attention. (GSH)."

Analysis of clinical studies shows that a significant decrease in GSH levels in the hippocampus causes early onset of AD before amyloid beta deposition and tau phosphorylation, which is supported by studies in transgenic animal models.

Main results and prospects of research

The special issue presents 12 reviews and research articles on OS and AD research from several internationally recognized laboratories. Key results include:

• Reducing the risk of developing asthma is associated with dietary intake of antioxidant supplements.
• Supplementation with GSH, composed of the amino acids glycine, cysteine, and glutamic acid, may be neuroprotective and reduce amyloid beta deposition or tau protein phosphorylation.
• Significant improvements in working memory in animal models of induced dementia by Marrubium vulgare extract suggest an effect on memory retention.
• Maintaining diversity in drug development in AD research is important to improve the flow of information from randomized clinical trials.

Combination therapy

One study examines the neuroprotective effect of combined treatment with epigallocatechin 3-gallate (EGCG) and melatonin (MT) in familial AD. In a three-dimensional in vitro model of a rare familial form of AD with a mutation in the presenilin-1 gene, the combination of EGCG and MT was more effective in reducing pathological markers compared to individual treatments.

Conclusion

Dr. Mandal emphasizes that the OS hypothesis in AD research deserves recognition, which can guide drug development to effectively reduce OS and preserve cognitive function. The discovery of OS as a precursor to amyloid beta and tau deposition places it at the center of effective therapeutic interventions, which is being explored in this topic.