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Alzheimer’s Disease (AD) accounts for 70-80 per cent of dementia cases and is the fifth leading cause of fatality. The disease is characterised by the accumulation of protein clumps in the brain, memory loss and cognitive defects, according to the department of Science and Technology.
Currently, there are very few treatment therapeutics available which provide temporary relief. Recently a few antibody- based drugs were approved but they offer limited relief to the patients. Although the role of various proteins in the development and progression of Alzheimer’s disease has been extensively studied, the role of microRNAs (miRNAs) whose discovery was awarded the Nobel Prize in Physiology or Medicine last year—remains poorly understood in the context of AD.
Addressing this gap, researchers from the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), an autonomous institute under the Department of Science and Technology (DST), have investigated altered miRNA expression in the AD brain. They also explored the potential of miRNAs as biomarkers for early, specific, and accurate clinical diagnosis of AD. As small non-coding RNAs, miRNAs are known to regulate multiple mRNAs, thereby influencing various biological pathways associated with health, disease, and the complex pathology of AD.
While the role of the various proteins in the development and progression of Alzheimer’s disease has been well studied, the progress of microRNAs (miRNAs) in AD is poorly comprehended, according to the researchers.
Here JNCASR scientists Prof. Madhu Ramesh and Prof Thimmaiah Govindaraju used a double transgenic Alzheimer’s disease mouse model to discover the novel miRNAs involved in the progression. They identified various miRNAs that are already in the Alzheimer’s disease compared to the normal brain which could potentially trigger the disease.
The current study offers valuable insights into Alzheimer’s disease by uncovering the regulatory role of miR-7a in controlling neuro-inflammation and ferroptosis via Klf4 targeting. Now we have Klf4 to stall neuro inflammation, said Prof Govindaraju.
Honokiol is a natural product found in bark and seed cones of Magnolia tree that targets Klf4 to stall neuroinflammation and ferroptotic cell death involved in AD. This demonstrates that the miR-7a-Klf4 axis is a novel target for AD and warrants further exploration to develop better therapeutics for the disease, stated the scientists.
The research shows that miR-7a suppresses Klf4, alleviating neuronal damage by modulating inflammation and ferroptosis-related (iron-dependent accumulation of lipid hydroperoxides) pathways. Targeting this axis with a blood–brain barrier-permeable compound like honokiol demonstrates therapeutic potential,” said Prof. Gireesh Gangadharan, Dept. of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, (MAHE).
With clinical evaluation, the developed miRNA mimic and small molecule, if proven safe and effective, could potentially cure AD, benefiting both patients and caregivers. The study unveiled the panel of upregulated and down regulated miRNA in AD which might serve as potential biomarkers for early clinical diagnosis of AD.
The results would significantly reduce the large socio-economic burden posed by this disease and would pave the path to treatment of neurodegenerative and neuroinflammatory disorders by targeting of neuroinflammation and ferroptosis.
Treatment gains more traction
With more trials happening, there is real momentum for treating the diseases that cause dementia. There are more potential new medicines being tested for Alzheimer’s disease, according to the website of Alzheimer’s Research UK.
Alzheimer’s researchers are hopeful that the wide range of drugs now being tested will lead to safer and more effective medicines. This builds on recent progress with lecanemab and donanemab, which are the first treatments to slow down the progression of Alzheimer’s. Further advances in drug development could lead to new treatment approaches – such as oral therapies or injections – that could be taken at home rather than in hospital, making treatment less disruptive for people and families living with dementia.
An annual review reports that 138 drugs are currently being tested – an increase of nearly nine per cent from last year. This news is promising, because the more drugs that scientists test, the greater the chance that new and effective medicines will soon become a reality for people living with dementia.
Drugs that could potentially help people in all stages of Alzheimer’s are being tested, from those in people showing no symptoms to those in later stages and with severe disease.
This latest report shows that there is hope on the horizon for people with Alzheimer’s after lecanemab and donanemab. However, it is essential to go further as progress is not fast enough for the millions of people affected by dementia, says a leading Alzheimer’s researcher.
The number of drugs entering early-stage clinical trials has jumped from 27 last year to 48 this year. These are looking at a wide range of approaches, including vaccines and engineered immune cells.
Most of the drugs target the underlying disease and are designed to slow the decline of memory loss rather than just treat the symptoms. This could ultimately help people to live independently for longer.
“There are more diverse experimental medicines than ever in the current pipeline targeting different processes. There’s an incredible range of drugs being tested to treat Alzheimer’s across the world, and I am hopeful we have the building blocks for a future where there will be a cure for this devastating disease”, he adds.
More clinical trials to test treatments
There are currently 182 clinical trials globally. Of these, over 40 are middle and late-stage trials that could publish their results this year. These include medicines that are already approved to treat other conditions and which are now being tested for Alzheimer’s.
One large trial is testing a pill form of semaglutide as a potential treatment for people with early Alzheimer’s. This drug is currently being used as an injection to manage type 2 diabetes and help with weight loss. Early research suggests that semaglutide could reduce inflammation in the brain, which can cause a cascade of damage that leads to Alzheimer’s disease and vascular dementia.
Barriers to developing new treatments
One of the major barriers to progress in developing new drugs is recruitment onto trials: globally more than 50,000 people are needed to populate all the current Alzheimer’s trials.
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