Promising therapies for Alzheimer's

For the past 15 years, chemical biologist Thimmaiah Govindaraju has been at war with some of the biggest scourges afflicting the human mind: neurodegenerative diseases. After developing several diagnostic tools and a promising drug molecule for Alzheimer's disease, his team at the Bengaluru-based Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) is all set to devise an altogether different strategy: targeting neuroinflammation.

Neurodegenerative diseases are characterised by complex disease pathology. Alzheimer's disease, for instance, involves an interaction of different mechanisms. In addition to protein misfolding and toxicity triggered by harmful amyloid-beta deposits, brain inflammation also plays a part in aggravating the condition. "One school of thought even says that the inflammation itself is causing the disease to manifest," says Govindaraju.

Inflammation, in general, is the body's response to toxins, pathogens, and injuries, and thus has a protective effect. "But for some reason, when these external or internal stimuli become too much, the inflammation also gets into overdrive. When it becomes excessive, it will not differentiate between normal and diseased cells and attacks every cell," he explains.

In a paper recently published in the Journal of Medicinal Chemistry (bit.ly/neuro-inflammation), the JNCASR team reports that it has found a way to inhibit neuroinflammation and tested its viability in lab-cultured cells.

In the case of neurodegenerative diseases such as Alzheimer's, toxic proteins, including amyloid-beta and tau, are formed in the brain. The brain has an inherent repair-and-clearance mechanism in the form of microglial cells. "But when the load is very high, microglia are over-activated, and release a class of molecules called pro-cytokines and excessive reactive oxygen species, leading to the formation of a multi-protein complex called NLRP3 inflammasome," Govindaraju says.

In the current work, the JNCASR scientists developed a strategy to target the NLRP3 inflammasome. The system they evolved would either prevent the multi-protein complex from forming or, if already formed, disassemble so that microglia were protected, which in turn would protect neuronal cells from general inflammation.

"This is a novel concept," says Govindaraju. The team has designed a ligand (a substance that binds with a biomolecule such as a protein) and mutated it by tweaking a few amino acids so that it tightly binds with some of the key proteins in the protein complex, leading to the disruption of the NLRP3 activity.

Govindaraju, who had designed a new drug molecule capable of protecting neuronal cells from amyloid-beta toxicity called TGR63 and licensed it to a U.S. firm in 2023, plans to test the ligand, named MNP2, in Alzheimer-induced transgenic mice.

Meanwhile, in an unrelated study, a team of German scientists has shown that targeting inflammasome is indeed a promising way to stop the progression of Alzheimer's. In a paper published in the February issue of the journal Immunity (bit.ly/AD-DZNE), researchers from the German Center for Neurodegenerative Diseases (DZNE) in Bonn, the Institute of Innate Immunity (III) at the University Hospital Bonn and other institutions showed that NLRP3 inhibition helps enhance microglia activity, leading to better degradation of amyloid-beta peptides by microglia. In a series of studies on cell culture, mice and tissue samples from patients, the scientists led by Róisín M. McManus and Michael T. Heneka, affiliated with DZNE and III, showed that this could lead to more effective therapies for Alzheimer's disease.

NLRP3 has two roles in cells. One, it controls inflammation and the production of inflammatory proteins called cytokines. "(In) the role we have now identified, it regulates microglial metabolism that has many downstream consequences for microglial function including their ability to phagocytize (engulfing and destroying) amyloid-beta," McManus says.

Their studies have identified previously unknown signalling pathways influenced by NLRP3. They found the NLRP3 regulates how microglia use nutrients and how these act on genes that significantly impact the function of microglia.

See also:

Untangling Alzheimer's disease