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A novel hybrid protein promotes Aβ clearance and reduces inflammatory response through MerTK

Caberoy, N. B.; Samentar, L. P.; Salazar, A.; Pan, P.; Etebar, K.; Choy, K.; Uddin, D.; Eliseeff, P.; Bugayong, A. M.; Garrido, J. A.; Emini, A.; Rock, N.

2021-11-04 molecular biology
10.1101/2021.11.03.467048 bioRxiv
Show abstract

Alzheimers disease (AD) is the worlds leading cause of dementia and the most common neurodegenerative disorder. Its major pathological features are amyloid beta (A{beta}) plaques, tau tangles, and neuroinflammation that eventually leads to massive death of nerve cells. Even with the multifactorial aspect of AD, the most accepted theory is that A{beta} is the driving force of AD pathogenesis. We engineered a novel hybrid protein that facilitates the phagocytosis of A{beta} and redirect its clearance to the noninflammatory Mer tyrosine kinase (MerTK) pathway. The novel hybrid protein facilitates robust uptake and clearance of A{beta} in BV2 microglia through MerTK receptor with reduced production of inflammatory factors and oxidative products. In APP/PS1 transgenic AD mouse model, intraperitoneal administration of the hybrid protein for two months results in significant reduction of A{beta} burden in the brain and protection of nerve cells from dying. Taken together, our results suggest that the novel hybrid may have the potential for AD treatment by targeting both A{beta} clearance and reduction of inflammation.

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