24-Feb-2021: JNCASR Scientists develop a new molecule that could be a potential drug candidate for the treatment of Alzheimer’s
Scientists have developed a small molecule that disrupts the mechanism through which neurons become dysfunctional in Alzheimer’s disease (AD). The molecule could be a potential drug candidate to halt or cure the leading cause of dementia (70-80%) worldwide.
In the Alzheimer's brain, abnormal levels of naturally forming protein clump together to form plaques that collect between neurons and disrupt cell function. This is caused by production and deposition of the amyloid peptide (Aβ) that accumulates in the central nervous system. The multifactorial nature of Alzheimer’s disease (AD) attributed to multifaceted amyloid toxicity has kept researchers from developing effective treatment.
A team of scientists led by Professor T. Govindaraju from Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), an autonomous institute of the Department of Science & Technology, Government of India, designed and synthesized a set of novel small molecules and identified a lead candidate which they found could reduce the toxicity of Amyloid Beta (Aβ) toxicity.
The detailed studies established the molecule called TGR63 as the lead candidate to rescue neuronal cells from amyloid toxicity. Remarkably, the molecule was also found to reduced amyloid burden in the cortex and hippocampus, or a complex part embedded deep into the temporal lobe, thereby reversing cognitive decline. This research has been published recently in the journal Advanced Therapeutics.
Currently available treatments provide only temporary relief, and there are no approved drugs that directly act on the disease mechanisms of Alzheimer’s disease. Thus, there is an unmet need to develop drug candidates to halt or cure Alzheimer’s disease.
Mice brain affected with Alzheimer’s disease when treated with TGR63 showed a significant reduction of amyloid deposits, validating its therapeutic efficacy. The mice also showed reduction of learning deficiency, memory impairment, and cognitive decline as revealed by distinct behavioural tests. These key attributes have validated the potential of TGR63 as a promising drug candidate for the treatment of AD.
AD severely affects the patients, families, caregivers and hence is a major societal and economic burden globally. The novel drug candidate TGR63 developed by the JNCASR team has potential as a promising drug candidate for AD treatment.
21-May-2020: IIT Guwahati discovers new ways to prevent memory loss due to Alzheimer
Researchers at Indian Institute of Technology (IIT) Guwahati has worked on out-of-the-box ideas that can help prevent or reduce short-term memory losses associated with Alzheimer’s disease.
The research team was headed by Prof. Vibin Ramakrishnan, Professor, Department of Biosciences & Bioengineering, IIT Guwahati, and Prof. Harshal Nemade, Professor, Department of Electronics and Electrical Engineering, IIT Guwahati. They studied the neurochemical principles of Alzheimer’s, and explored new ways to prevent accumulation of neurotoxic molecules in the brain that are associated with short-term memory loss.
The IIT Guwahati team reports interesting methods such as application of low-voltage electric field, and the use of ‘trojan peptides’ to arrest aggregation of neurotoxic molecules in the brain. The scientists are assisted by research scholars Dr. Gaurav Pandey and Mr. Jahnu Saikia in their work. The results of their studies have been published in reputed journals such as ACS Chemical Neuroscience, RSC Advances of Royal Society of Chemistry, BBA and Neuropeptides.
The development of a cure for Alzheimer’s disease assumes importance India as it has the third highest number of Alzheimer’s patients in the world, after China and US, with more than four million people falling prey to the memory loss associated with it. While current treatments only alleviate some of the symptoms of the disease, there is no disruptive therapeutic approach yet that can treat the underlying causes of Alzheimer’s.
“Approximately hundred potential drugs for treatment of Alzheimer’s disease have failed between 1998 and 2011, which shows the gravity of the problem,” says Dr. Ramakrishnan, who participates in worldwide efforts at finding cures for the disease.
A defining hallmark of Alzheimer’s is the accumulation of amyloid beta peptides in the brain. Dr. Ramakrishnan and Dr. Nemade seek methods to reduce the accumulation of these peptides, in order to arrest the progression of Alzheimer’s.
In 2019, the IIT Guwahati scientists found that application of a low-voltage, safe electrical field can reduce the formation and accumulation of toxic neurodegenerative molecules that cause short-term memory loss in Alzheimer’s disease. They found that external electric/magnetic field modulates the structure of these peptide molecules, thereby preventing aggregation.
“Upon exposure to electric field, we could retard the degeneration of nerve cells to an extent of 17–35%. Objectively, this would translate to about 10 years delay in the onset of the disease”, says Dr. Ramakrishnan.
Working further in this area, the scientists explored the possibility of using ‘Trojan peptides’ to arrest aggregation of these neurotoxic molecules. The idea of using ‘Trojan peptide’ comes from mythological “Trojan Horse” used as subterfuge by the Greeks in the battle of Troy. The researchers have designed Trojan peptides by adopting a similar approach of ‘deceit’ to impede the aggregation of the amyloid peptide, arrest the formation of toxic fibrillar assemblies, and reduce poisoning of nerve cells that leads to memory loss.
“Our research has provided a different path that may extend the onset of the Alzheimer’s disease. However, it would take testing in animal models and clinical trials before bringing in such new therapeutic approaches into human treatment” say project coordinators, Dr. Ramakrishnan and Dr. Nemade.
30-Apr-2020: JNCASR scientists develop a natural product based Alzheimer inhibitor
Scientists from Jawaharlal Nehru Centre For Advanced Scientific Research (JNCASR) an autonomous institute under the Department of Science & Technology (DST), Govt. of India have modified the structure of Berberine, a natural and cheap product similar to curcumin, available commercially, into Ber-D to use as a Alzheimer’s inhibitor. Their research work has been published in the scientific journal iSceince.
Alzheimer’s disease is the most prevalent neurodegenerative disorder and accounts for more than 70% of all dementia. The multifactorial nature of the disease attributed to multifaceted toxicity has made it difficult for researchers to develop effective medication.
Prof. T. Govindaraju, a Swarnajayanti fellow from JNCASR, led his team in the quest to discover natural product based therapeutic candidates for Alzheimer’s disease, and selected isoquinoline natural product berberine found in India and China and used in traditional medicine and other applications. However, berberine is poorly soluble and toxic to cells. So they modified berberine to Ber-D, which is a soluble (aqueous), antioxidant. They found it to be a multifunctional inhibitor of multifaceted amyloid toxicity of Alzheimer’s disease.
Protein aggregation and amyloid toxicity predominantly contribute to multifaceted toxicity observed in neuronal cells, including generation of reactive oxygen species (ROS), mitochondrial dysfunction, interfering with synaptic signaling, and activation of premature cell death. The JNCASR team developed this multifunctional inhibitor to ameliorate in cellulo multifaceted toxicity.
JNCASR scientists develop a natural product based Alzheimer inhibitor The structural attributes of Ber-D are such that they prevent the generation of reactive oxygen species (ROS) and rescue biomacromolecules from oxidative damage. Ber-D inhibits aggregations of metal-dependent and -independent Amyloid beta (Aβ) (which are the peptides of amino acids crucially involved in Alzheimer's disease as the main component of the amyloid plaques found in the brains of people with Alzheimer's disease).
The team developed Ber-D to effectively target multifaceted Aβ toxicity of Alzheimer’s disease. Berberine has 4 Phenolic hydroxyl groups which are methylated, hence water-insoluble. Natural product berberine was subjected to demethylation to obtain water-soluble polyphenolic derivative Ber-D. Treatment of berberine with demethylation agent BBr3(Boron tribromide) gave Ber-D Because of demethylation of berberine, 4 phenolic groups are free, increase water solubility, antioxidant property, and Cu-coordination to ameliorate multifaced toxicity of Alzheimer’s disease Detailed studies showed that Ber-D modulated Aβ toxicity of Alzheimer’s disease. Ber-D treatment averts mitochondrial dysfunction and corresponding neuronal toxicity contributing to premature apoptosis (cell death) making Ber-D a potential therapeutic candidate to ameliorate multifaceted Aβ toxicity in Alzheimer’s disease.
The antioxidant Ber-D efficiently quenched both Reactive nitrogen species(RNS) & reactive oxygen species (ROS) and prevent DNA damage, protein oxidation, and lipid peroxidation, which cause numerous adverse biochemical cascade reactions leading to neuronal death. Ber-D inhibits the formation of toxic Aβ fibrillar aggregates and protects mitochondria from dysfunction, one of the major causes of neuronal death. Their design strategy of synthetically transforming berberine to Ber-D, a multifunctional antioxidant and aggregation modulator, effectively ameliorate multiple Aβtoxicity both in vitro and in cellulo conditions.
These multifunctional attributes make Ber-D a promising candidate for developing effective therapeutics to treat multifaceted toxicity of Alzheimer’s disease.