Annie Schmidt
Annie Schmidt
Annie Schmidt
Helios Scholar
School: Arizona State University
Hometown: Phoenix, Arizona
Mentor: Matt Huentelman, Ph.D.

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Small Molecule Stimulation of TREM2 as a Mechanism for Alzheimer’s Disease Prevention

Alzheimer’s disease (AD) is a neurodegenerative disease that impacts over 5 million Americans and their caregivers and of the top ten causes of death, it is the only one that cannot be prevented, halted, or reversed. Because the causes of AD are not fully understood, the study of rare genetic variants could lead to new disease-altering therapies. Our work focuses on identifying drugs that stimulate the protein product of the TREM2 gene (Triggering Receptor Expressed on Myeloid Cells-2) as a potential AD therapeutic.

In healthy systems, TREM2 increases anti-inflammatory response, phagocytosis, and microgliosis of brain plaque by signaling through its partner protein TYROBP. The rare R47H variant of the TREM2 protein has been shown to decrease binding affinity and impair mechanisms that protect against axonal dystrophy and cognitive decline. It also increases AD risk by three to four times, comparable to the strongest known genetic association with late-onset AD, conferred by the APOE4 allele. Since TREM2 is most highly expressed in microglia, these findings highlight the role of innate immunity in the progression of AD and reveal a potential therapeutic pathway.

We previously identified three “top hit” compounds that stimulate the TREM2/TYROBP pathway. Our aim was to build on these results and identify agonists of TREM2 (R47H) because it is likely that individuals homozygous for this rare variant would be the first to receive treatment in experimental trials.

We utilized site-directed mutagenesis to subclone a plasmid encoding TREM2 (R47H) into a Lentiviral vector for subsequent transduction of BW5147.3 lymphocytes. This was followed by a luciferase assay to measure changes in firefly luciferase transcription downstream of the system’s NFAT promoters (Nuclear Factor of Activated T Cells). To isolate the effects of TREM2 (R47H) and TYROBP stimulation, the luminescence of experimental screen and control lines were compared. The screen line included TREM2 (R47H), TYROBP, and NFAT reporter, while the control line included only NFAT reporter. Final data is reported as a ratio of screen luminescence to control luminescence. 

Further analysis of these drugs in vivo and in clinical trials could assist in the treatment and prevention of AD, particularly for TREM2 (R47H) homozygotes and others at increased risk of developing Alzheimer’s disease.