Wed. Jun 19th, 2024

An improved alzheimer’s medication that has no inflammatory side effects, developed by Korean scientists

Without causing inflammatory side effects or synapse loss, the researchers think this method could be a breakthrough in the treatment of Alzheimer's disease. 

The neurotoxic inflammatory adverse effects of standard treatments are avoided by the novel medication. Based on its capacity to reduce A plaque burden in AD patients, Aduhelm just became the first medication for Alzheimer’s disease (AD) to receive FDA approval in the United States. Its influence on cognitive development is still debatable, though.

ARIA-E and ARIA-H, which are likely connected to inflammatory reactions in the brain induced by the A antibody binding Fc receptors (FCR) of immune cells including microglia and macrophages, are major adverse effects that occurred in about 40% of patients who had this antibody treatment.

By resulting in neuronal cell death and the destruction of synapses by activated microglia, these inflammatory side effects have the potential to exacerbate cognitive impairment in Alzheimer’s disease patients. The current A antibody-based immunotherapy runs the danger of doing more harm than good because of its inflammatory adverse effects.

In order to solve these problems, a group of scientists at the Korea Advanced Institute of Science and Technology (KAIST) in South Korea developed A-Gas6, a novel fusion protein medication that effectively eradicates A through a totally different mechanism than A-antibody-based immunotherapy. A-Gas6 not only removed A more efficiently in a mouse model of Alzheimer’s disease, but it also prevented the neurotoxic inflammatory side effects related to traditional antibody therapies.

The results were just released in Nature Medicine.

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

“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” Prof. Kim and Chung said. “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 Aβ plaques.”

Due to the strong expression of TAM phagocytic receptors on these two important phagocytes in the brain, the scientists showed that the resultant A-Gas6 driven A engulfment activated both microglial and astrocytic phagocytosis. Without exhibiting any symptoms of inflammation or neurotoxicity, the “A-Gas6” enabled the vigorous absorption of A. Additionally, they demonstrated that A-Gas6 significantly decreased excessive microglia synapse removal, which therefore resulted in superior behavioural rescues in AD model mice.

Researchers further demonstrated that the intrathecal delivery of Gas6 fusion protein significantly reduced cerebrovascular amyloids and decreased microhemorrhages using a mouse model of cerebral amyloid angiopathy (CAA). As a result, aAb-Gas6 is an effective therapeutic agent for removing A without escalating microhemorrhages caused by CAA.

Based upon the method of creating chimeric Gas6 fusion proteins that would eliminate harmful aggregates from the nervous system, Professors Kim and Chung established “Illimis Therapeutics.” Through this enterprise, they intend to continue creating other Gas6-fusion proteins to cure the symptoms of AD in Tau as well as Ab.

By Editor

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