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Alzheimer’s Treatment: New Frontiers From Algal Products

Here I am! I am a biologist and I have been involved in biomedical scientific research for many years. Writing has always been my passion.

Alzheimer’s disease is the most common neurodegenerative disorder currently affecting 55 million people worldwide, according to World Alzheimer Report 2021, which is still without effective treatment.

Sodium oligomannate (GV-971), a natural product derived from brown seaweed, is the first new compound approved for the treatment of Alzheimer's disease since 2003. So far, its use in humans has only been authorized in China. If the promising results of the first study to be completed are confirmed by further observations, GV-971 could be approved by government drug agencies in other countries.

Alzheimer's is characterized by cognitive impairment and inability to perform the actions of daily life

Alzheimer's is characterized by cognitive impairment and inability to perform the actions of daily life

What is known about Alzheimer’s

Alzheimer’s disease is so-called by the name of a German psychiatrist, Dr. Alois Alzheimer, who described the typical symptoms in 1901. A slow and irreversible memory loss, accompanied by cognitive impairment and inability to perform the actions of daily life, often evolving into dementia, are the peculiar characteristics of Alzheimer’s patients.

The disease is the result of many factors, some of genetic and environmental origins others resulting from a disordered lifestyle and an unbalanced diet.

The scientists have designed seven hypotheses to explain the occurrence of sporadic and not-inherited Alzheimer’s forms. They are conducible to:

1. diminution of acetylcholine release, an important neurotransmitter involved in the memory formation process;

2. deposition of amyloid protein aggregates, which is responsible for the formation of amyloid plaques;

3. formation of tau protein tangles;

4. oxidative stress;

5. inflammation;

6. environmental pollution (ie. by heavy metals);

7. metabolic disorders due to cholesterol levels, type 2 diabetes, and obesity.

Despite the numerous aspects involved in the onset and progression of the disease, all therapies used so far have failed.

Where the new research is going

The risk of developing early-onset familial forms depends on the inheritance of specific gene mutations. The best characterized are at the level of the apolipoprotein APOEε4, amyloid-protein-precursor APP, presenelin-1 PSEN1, and/or presenelin-2 PSEN2, gene sequences.

Having one of these mutations at birth increases the probability of developing Alzheimer’s later in life, but there is no definite cause-effect relationship. Being aware of it allows people to stay alert and don’t underestimate any of the early modifications in amnestic capability.

However, it is very difficult to establish the onset of the disease in that cases are independent of genetic predisposition.

The research in the last time is fully oriented towards the identification of biomarkers, a sort of biological indicator, that could help for an early diagnosis, in some cases many years before clinical signs will be evident.

The biomarkers currently under study are any little change in brain structure conformation visible by magnetic resonance imaging (MRI), the presence of protein aggregates especially amyloid or tau proteins relievable by positron emission tomography (PET), or by dosage in cerebrospinal fluid or/and blood.

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Even if the gold standard of Alzheimer’s diagnosis is the presence of amyloid plaques and tau tangles in post-mortem brain observation, the possibility to identify subjects at risk for developing the disease could allow for starting therapies that could slow down the progression of symptoms and ameliorating lifestyle of the patients.

The drugs currently in use treat the symptoms but not the causes of the disease

The drugs currently in use treat the symptoms but not the causes of the disease

Alzheimer’s old and new therapies

The first therapeutics introduced for the treatment of Alzheimer’s have been compounds act to increase acetylcholine levels to counteract memory loss. Among these so-called acetylcholinesterases inhibitors, there are drugs still in use donepezil, rivastigmine, and galantamine. Such compounds are only symptomatic relieves, because of their ability in reducing cognitive and behavioral symptoms, in the mild to moderate stages of the disease.

Towards the end stage of dementia, are used other drugs to reduce excitability, such as memantine, and antipsychotics.

Multi-target drugs have also developed that regulate other enzymatic and biosynthetic pathways upstream, altering the disease’s development. These compounds are named disease-modifying drugs, and those under study could block amyloid deposition and tau protein aggregation. The monoclonal antibody Aducanumab seems can inhibit amyloid plaque formation, reversing the course of the disease. It has been approved by Food and Drug Administration (FDA) in the United States since 7 June 2021, despite the uncertainty of the clinical trials and against the recommendation of an expert advisory committee.

Many efforts are now oriented to the study of a new strategy of intervention that takes into account the quality of patients ‘life with particular attention to diet and research of natural products with neuroprotective activity.

Among the most promising new therapeutics, there is sodium oligomannate (GV-971), a sugar extracted from brown seaweed that was able to improve cognitive ability in patients with mild to moderate AD in phase 3 clinical trials, long-lasting 9 months, with no safety issues.

GV-971 was developed by Shanghai Green Valley Pharmaceuticals and approved for first clinical use in patients with mild to moderate AD by the National Medical Products Administration (NMPA; Chinese equivalent of the FDA) in November 2019.

Alzheimer’s disease is the most common neurodegenerative disorder currently affecting 55 million people worldwide

Alzheimer’s disease is the most common neurodegenerative disorder currently affecting 55 million people worldwide

Why sodium oligomannate? How long so far?

Recent studies both in animals and humans have demonstrated the importance of a healthy diet to maintain the body safe and free of inflammatory processes. The choice falls on nutrients capable of restoring the balance between the products of microbic metabolism at the intestinal level. So because the alteration of the equilibrium is one of the trigger events of inflammation. A condition known as 'intestinal dysbiosis' occurs when the population of good bacteria that populate the gut biome decreases to the advantage of bad microorganisms.

The intestinal tract is called “the second brain” because of its dense network of neurons and nerve connections. In addition, resident microorganisms release bioactive substances in the same way as neurotransmitters, and there is an active exchange of information between the brain and gut.

Scientists have observed in experimental Alzheimer's models, that intestinal dysbiosis leads to the accumulation of two amino acids, phenylalanine, and isoleucine in the peripheral blood.

As a consequence of this accumulation, the body for defense produces a particular type of reactive molecules by the immune system (our bodyguard), the Th1 cells, where “h” stands for 'helper'. Through the bloodstream, these cells reach the brain where they trigger an inflammatory chain reaction involving microglia cells, the first resort against enemy attacks in the brain.

The same study showed that sodium oligomannate (GV-971), a sugar extracted from brown seaweed can prevent the development of the inflammatory process in the gut and restore the balance between the various components of the intestinal microbiota. It also acts locally in the brain by reducing the immune response and inflammation as well as the formation of new amyloid fibrils, helping to degrade those already formed. All with a general improvement in cognitive abilities already after 4 weeks of treatment.

What about sodium oligommanate effects in humans?

The same effects were described in the first phase 3 clinical trials.

In this study, participants were observed for 36 weeks and after oral administration (450 mg twice daily) of sodium oligomannate, showed a significant recovery in cognitive abilities compared to controls given a known drug or placebo (a substance with no effect).

Daily intake of fibres from vegetables keeps the gut healthy

Daily intake of fibres from vegetables keeps the gut healthy

Conclusion

Finally, gut dysbiosis can be considered an important trigger event for the development of systemic inflammation with brain involvement. So neuroinflammation is one of the peculiar characteristics of Alzheimer’s and other neurodegenerative diseases, much can be done by improving the diet by favoring anti-inflammatory foods.

© 2022 Immacolata Vecchio

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