Anavex Life Sciences Corp (AVXL)

[sokol]

Conducting an Alzheimer’s Prevention Trial.

Possibly biomarkers may be used to conduct such an AD prevention trial.

Oxidized DNA, RNA, protein and lipid products may be used as possible disease progression markers.

1. Oxidative toxicity in diabetes and Alzheimer’s disease: mechanisms behind ROS/ RNS generation

Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer’s disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers. Although the oxidative stress has been anticipated as a main cause in promoting both AD and T2DM, multiple pathways could be involved in ROS production. The focus of this review is to summarize the mechanisms involved in ROS production and their possible association with AD and T2DM pathogenesis and progression. We have also highlighted the role of current treatments that can be linked with reduced oxidative stress and damage in AD and T2DM.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606025/

2. Oxidative stress and the amyloid beta peptide in Alzheimer's disease

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly.

.....The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aß peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aß peptide and surrounding molecules in terms of oxidative damage......

https://pubmed.ncbi.nlm.nih.gov/29080524/

3. Oxidative Stress, Amyloid-ß Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease

...Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-ß peptide, Aß1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aß1-42, but not in Aß1-42-poor regions, and was among the first to demonstrate Aß peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. ...

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad170543

4. Future Therapeutic Perspectives into the Alzheimer’s Disease Targeting the Oxidative Stress Hypothesis

Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aß) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary.

https://mdpi-res.com/d_attachment/molecules/molecules-24-04410/article_deploy/molecules-24-04410.pdf


5. Clinical Relevance of Biomarkers of Oxidative Stress

See p. 1161 (P. 18) - Ox-LDL, MDA and 8oxoGuo biomarkers are highest evidence levels for Alzheimer's

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657513/pdf/ars.2015.6317.pdf

6. Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease

Ox-LDL Biomarker

Our data extend previous reports regarding the inflammatory markers in the plasma and CSF of patients with AD and provide good evidence that levels of ACT, IL-6, MCP-1 and oxLDL in plasma and CSF might be candidates as biomarkers for monitoring the inflammatory process in AD.

https://pubmed.ncbi.nlm.nih.gov/12826739/

7. Blood markers of oxidative stress in Alzheimer's disease

MDA Biomarker

MDA arises largely from the peroxidation of PUFA. It exists either in a free form or in bound to proteins. Free MDA in vivo is rapidly metabolized in tissues. A number of studies document elevated levels of MDA in AD and MCI in the plasma/serum [34–42]. Increased concentrations of thiobarbituric reactive substances in the serum [43] or erythrocytes [44, 45] of patients with AD were also documented. In contrast, there are studies that did not find differences in the concentration of MDA between AD patients and controls [46–51].

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823422/

8. The Significance of 8-oxoGsn in Aging-Related Diseases

8-oxoGsn Biomarker

Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson’s disease, Alzheimer’s disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505272/