Award Date


Degree Type


Degree Name

Doctor of Philosophy (PhD)


Life Sciences

First Committee Member

Nora Caberoy

Second Committee Member

Andrew Andres

Third Committee Member

Jeffery Shen

Fourth Committee Member

Frank van Breukelen

Fifth Committee Member

Gary Kleiger

Number of Pages



Alzheimer’s disease (AD) is the world’s leading cause of dementia and the most common neurodegenerative disorder. Its major pathological features are amyloid beta (Aβ) plaques, Tau tangles, and neuroinflammation that eventually leads to massive death of nerve cells. Even with the multifactorial aspect of AD pathogenesis, the most accepted theory is that Aβ is the driving force of AD pathogenesis. In the brain, Aβ is primarily removed by immunocompetent cells called microglia through phagocytosis. This process is mediated by pattern recognition receptors (PRRs) including receptor for advanced glycation end products (RAGE). Phagocytosis through PRRs results to the release of inflammatory factors that eventually lead to the death of nerve cells. Previously, the Caberoy Laboratory has identified Tubby protein that facilitates the phagocytosis of cellular debris in the retina through Mer Tyrosine Kinase (MerTK) receptor. In contrast to RAGE and other PRRs, phagocytosis through MerTK is considered silent because it does not result in an inflammatory response. To divert the clearance of Aβ from inflammatory RAGE to the non-inflammatory MerTK pathway, we created a hybrid protein containing the minimal phagocytic domain (MPD) of Tubby that can recognize MerTK and the Aβ binding peptide (AβBP) that can specifically bind to Aβ. We have shown that the novel hybrid protein facilitates robust uptake and clearance of Aβ in BV2 mouse microglial cells through MerTK receptor. This MerTK-mediated phagocytosis of Aβ in BV2 cells leads to a reduction in the levels of inflammatory factors and oxidative products. In a triple transgenic AD mouse model, daily intraperitoneal administration of the hybrid protein for one month results to a significant reduction of Aβ burden in the brain, reduction of interleukin (IL)-6 in the blood, and protection of nerve cells from dying without causing toxicity. Over-all, we have shown the utility of the hybrid protein as a potential AD treatment by targeting both Aβ clearance and reduction of inflammation. This project also demonstrates that the engineering of hybrid proteins to act as adapter molecules between a specific ligand and a particular receptor can be used as a promising strategy for the clearance of harmful disease-causing metabolic products such as Aβ in AD.


Alzheimer’s disease; Amyloid beta (Aβ); Mer Tyrosine Kinase (MerTK); Microglia; Novel protein; Phagocytosis


Biology | Cell Biology | Molecular Biology

File Format


File Size

4600 KB

Degree Grantor

University of Nevada, Las Vegas




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Available for download on Monday, May 15, 2028