Drug For Alzheimer's Disease Found Without Inflammatory Side Effects

The researchers of a recent, developed a novel fusion protein drug aAb-Gas6 which helps in efficiently eliminating Ab through a different mechanism. 

Tanya Srivastava
Written by: Tanya SrivastavaPublished at: Aug 05, 2022Updated at: Aug 05, 2022
Drug For Alzheimer's Disease Found Without Inflammatory Side Effects

Aduhelm is a monoclonal antibody that targets amyloid beta (A). It was recently found by the US Food and Drug Administration as the first treatment for the Alzheimer's disease (AD). Around 40 percent of the patients treated with this antibody experience serious side effects. These side effects may include cerebral edemas and hemorrhages, which are likely related to inflammatory responses in the brain. Therefore, current Ab antibody-based immunotherapy holds the inherent risk of doing more harm than good due to its inflammatory side effects.

The researchers of a recent study published in the journal Nature Medicine, developed a novel fusion protein drug aAb-Gas6 which helps in efficiently eliminating Ab through a different mechanism. 

In a mouse model of AD, aAb-Gas6 helped in removing Ab with higher potency. Additionally, it also circumvented the neurotoxic inflammatory side effects which were associated with conventional antibody treatments of the disease.

Talking along the lines paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST said, "FcR activation by Ab targeting antibodies induces microglia-mediated Ab phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues." 

"Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Ab in the brain. Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Ab plaques." Prof. Kim and Chung added.

Drug For Alzheimer's Disease Found Without Inflammatory Side Effects

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The team demonstrated that that aAb-Gas6 promoted the robust uptake of Ab without showing any signs of inflammation and neurotoxicity. In addition, they also showed that aAb-Gas6 substantially reduced the excessive synapse elimination by microglia, consequently leading to better behavioral rescues in alzheimer's disease model mice.

Professors Kim and Chung concluded by nothing, "We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses."

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