Researchers at the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), an autonomous institute under the Department of Science and Technology (DST), Government of India, have identified a novel therapeutic target for Alzheimer’s Disease (AD). The study explores RNA-based and small molecule-based therapeutic approaches that could accelerate the drug discovery process for the condition.
Alzheimer’s Disease accounts for 70–80 per cent of all dementia cases and is the fifth leading cause of death globally. The disease is marked by the accumulation of protein clumps in the brain, progressive memory loss, and cognitive decline. Current therapeutic options are limited and provide temporary relief, with recent antibody-based drugs offering modest benefits.
While the role of various proteins in AD has been extensively studied, the involvement of microRNAs (miRNAs) remains underexplored. miRNAs, which are small non-coding RNAs, are known to regulate multiple gene expression pathways and disease mechanisms.
In the study published in NAR Molecular Medicine, researchers Madhu Ramesh and Prof. Thimmaiah Govindaraju used a double transgenic AD mouse model to identify altered miRNAs in the AD brain. They found a significant increase in miR-7a levels, which targets the gene Klf4, a regulator of gene expression linked to AD.
“The current study offers valuable insight into Alzheimer’s disease by uncovering the regulatory role of miR-7a in controlling neuroinflammation and ferroptosis via Klf4 targeting,” said Professor T Govindaraju.
The researchers developed a miRNA-based therapeutic that mimics miR-7a and silences Klf4 expression, helping reverse AD-related pathologies. In addition, they used Honokiol, a natural product found in the Magnolia tree, to modulate the miR-7a-Klf4 pathway.
According to the study, miR-7a suppresses Klf4, alleviating neuronal damage by regulating inflammation pathways such as NF-κB, iNOS, and NLRP3, and ferroptosis, an iron-dependent cell death process.
“Targeting this axis with a blood–brain barrier-permeable compound like honokiol demonstrates therapeutic potential,” said Prof. Gireesh Gangadharan, Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education (MAHE).
The study also identified a panel of upregulated and downregulated miRNAs in AD, which could serve as potential biomarkers for early diagnosis. With clinical validation, the combination of miRNA mimic and Honokiol may offer a treatment pathway and possibly a cure for Alzheimer’s Disease.
The findings have the potential to reduce the socio-economic burden posed by AD and provide a foundation for treating other neurodegenerative and neuroinflammatory disorders.