A hibiscus compound may help remove toxic plaque build-up in Alzheimer’s

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  • Accumulation of toxic aggregates of the beta-amyloid proteins in certain brain regions is often linked to the decline in cognitive function characteristic of Alzheimer’s disease.
  • Studies suggest that impaired clearance or removal of beta-amyloid may contribute to the accumulation of beta-amyloid in Alzheimer’s disease.
  • A recent study shows that gossypetin, a flavonoid present in the flower of a hibiscus species, facilitated the clearance of beta-amyloid in the brain of an Alzheimer’s mouse model.
  • Treatment with gossypetin also attenuated deficits in memory and learning in the mouse model, highlighting the therapeutic potential of this compound in Alzheimer’s disease.

In the absence of effective treatments for Alzheimer’s disease, current projections suggest that the number of individuals in the United State living with this neurodegenerative condition could more than double by 2050.

This highlights the urgent need for novel, efficacious treatments for Alzheimer’s disease.

A recent study conducted in mice, whose results appear in the journal Alzheimer’s Research & Therapy, suggests that gossypetin, a compound derived from the flower of the roselle plant, a hibiscus species, may hold promise as a therapeutic agent for Alzheimer’s.

The study found that gossypetin helped reduce cognitive deficits and lower beta-amyloid levels in brain regions involved in cognitive function in a mouse model of Alzheimer’s disease.

Alzheimer’s disease is characterized by deficits in cognitive function, including memory, thinking, and reasoning, that gradually worsen over time. These cognitive deficits are associated with the formation of aggregates of misfolded beta-amyloid protein.

Repeating units of beta-amyloid, also known as monomers, initially form small aggregates called oligomers, which can then aggregate to form plaques.

Researchers have hypothesized that beta-amyloid oligomers are responsible for the damage to neurons and the loss of synapses, the sites where neurons connect and communicate with each other, observed in Alzheimer’s disease.

Given the role of beta-amyloid accumulation in the development of Alzheimer’s disease, scientists have developed drugs that target pathways involved in the production of this protein.

However, most drugs targeting the synthesis of beta-amyloid have failed to show sufficient clinical efficacy.

In addition to the production of beta-amyloid, studies suggest that impaired removal or clearance of beta-amyloid may also contribute to the accumulation of this protein. As a result, there has been growing interest in developing therapies, including antibodies, that facilitate the clearance of beta-amyloid plaques or oligomers.

There are multiple different mechanisms for the clearance of beta-amyloid, including degradation by enzymes or via transportation to the periphery.

Glial cells, which are the major cell type in the brain besides neurons, play an important role in the clearance of beta-amyloid.

For instance, astrocytes and microglia, which are types of glial cells, secrete enzymes that can break down beta-amyloid. In addition, microglia and astrocytes can also engulf damaged cells, debris, and misfolded proteins, such as beta-amyloid, by a process called phagocytosis.

Thus, drugs that facilitate the clearance of beta-amyloid by glial cells could potentially serve as disease-modifying drugs for Alzheimer’s disease.

In the present study, researchers assessed the impact of gossypetin, a flavonoid found in a part of the hibiscus flower, on the production and clearance of beta-amyloid.

Previous studies have shown that a higher intake of flavonoids, which are present in commonly consumed fruits, vegetables, and beverages, may reduce the risk of Alzheimer’s disease. Moreover, in vitro studies have shown that flavonoids can inhibit the aggregation of beta-amyloid.

In the present study, the researchers used the 5xFAD mouse model to examine the effects of gossypetin. The 5xFAD mouse model expresses two human genes carrying a total of five mutations that are common in familial Alzheimer’s disease.

To examine the effects of this flavonoid, the researchers administered either gossypetin or vehicle daily to 5xFAD mice for 13 weeks. The 5xFAD mice treated with gossypetin showed lower deficits in spatial learning and memory than the vehicle-treated animals.

Treatment of 5xFAD mice with gossypetin also reduced the size and number of beta-amyloid plaques in the hippocampus and cortex, brain regions involved in cognition. Moreover, the administration of gossypetin also led to a decrease in beta-amyloid monomers and oligomers in these brain regions.

The beta-amyloid protein — as monomers — occurs in different forms of varying length, with certain forms being more prone to forming toxic aggregates. In the present study, the researchers found that gossypetin reduced the levels of all forms of beta-amyloid.

The lower beta-amyloid levels observed in the brains of gossypetin-treated 5xFAD mice were not accompanied by changes in the levels of enzymes involved in the production of beta-amyloid.

These results suggest that the improvements in cognitive function in the mouse model of Alzheimer’s due to gossypetin treatment were likely mediated by modulating the clearance, instead of the synthesis, of beta-amyloid.

Given the possible effects of gossypetin on the clearance of beta-amyloid, the researchers examined the impact of gossypetin on microglia in 5xFAD mice.

Gliosis, involving the activation and proliferation of astrocytes and microglia in response to damage to brain cells, is a hallmark of Alzheimer’s. In the present study, treatment with gossypetin reduced gliosis in the hippocampus and cortex of 5xFAD mice.

The researchers also found that gossypetin increased the levels of markers of phagocytosis in the hippocampus and cortex of the 5xFAD mouse model. In addition, pre-treatment of laboratory-cultured microglia from mouse brains with gossypetin increased the phagocytosis of the beta-amyloid protein.

These results suggest that gossypetin treatment increased the phagocytic activity of microglia to facilitate the clearance of beta-amyloid.

The researchers noted that they were unable to examine the impact of gossypetin on the function of astrocytes and neurons due to the specific techniques used in the study. In other words, in addition to modulating the phagocytic activity of microglia, gossypetin could potentially improve cognitive function through other mechanisms.

Prof. Kyong-Tai Kim, from the Department of Life Sciences at Pohang University of Science and Technology in the Republic of Korea, who is one of the study authors, notes that:

“We have confirmed that removing [beta-amyloid] aggregates deposited in the brain is effective in preventing and treating dementia. Gossypetin from hibiscus will contribute to the development of a safe and affordable drug for patients suffering from [Alzheimer’s disease].”

Commenting on the research, Dr. Raymond J. Tesi, president, CEO, and acting CMO of INmune Bio, a clinical stage immuno-oncology company, told Medical News Today that “[g]ossypentin is an antioxidant” and that “antioxidant therapy is one of the ‘other than amyloid’ therapeutic strategies out there.”

“The others include targeting neuroinflammation, improving mitochondrial function, decreasing insulin resistance/ improving glucose metabolism, preventing lysosomal dysfunction, and improving cholesterol metabolism,” he added.

“In the ‘other than amyloid’ world, every one of these ’causes’ of [Alzheimer’s disease] must be tested,” Dr. Tesi insisted. “Gossypentin now has evidence that it works in animals. With luck, the drug will be tested in man. Only then will we know if there is a ‘new kid on the block!’”

These experiments were conducted in a mouse model of familial Alzheimer’s, which accounts for less than 5% of all Alzheimer’s disease cases.

The remaining overwhelming majority of Alzheimer’s cases are sporadic, meaning that they occur in individuals without a family history of Alzheimer’s disease, and are likely to be caused by an interaction between genetic and environmental risk factors.

The 5xFAD model is based on mutations present in common types of familial Alzheimer’s disease and does not recapitulate certain features of sporadic Alzheimer’s.

Dr. Wolfgang Streit, a neuroscientist at the University of Florida, not involved in the current study, cautioned that the study results may not be widely applicable.

“Regarding [the] significance for human sporadic Alzheimer’s disease — the prevalent form of Alzheimer’s disease — the study is insignificant,” he opined.

“Data were generated in highly artificial model systems that do not mimic the pathogenesis or progression of human Alzheimer’s disease. Conclusions are therefore not justified. Any implications for human treatments are speculative,” he warned.

Similarly, Dr. Tesi noted: “The FAD 5X mouse is a genetically driven model of the overexpression of [beta-amyloid]. I am not sure if this model is relevant to the disease in man. Sure, mice and men both have amyloid. The [accumulation of beta-amyloid] in the FAD 5X mouse is genetically driven. [Beta-amyloid] in man is driven by everything but genetics.”

He also cast some doubt on the notion that beta-amyloid is the main culprit in Alzheimer’s, which might, in turn, mean that researchers are not developing the most helpful therapeutics:

“Forty percent of normo-cognitive elders [older individuals with normal cognitive function] die with amyloid in their brains. Amyloid is not the smoking gun of [Alzheimer’s disease]. If it was, then every clinical trial using a therapeutic anti-amyloid antibody would have helped patients treated with the drug. In fact, a majority of the trials have been negative.”

“I am not ready to completely dismiss the amyloid hypothesis of [Alzheimer’s disease] — but I do view it with a healthy measure of skepticism. There is more to [Alzheimer’s disease] than [beta-amyloid]. This model is all about [beta-amyloid],” said Dr. Tesi.

Read the full article here

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