Validation of Drug Candidates for Enhancing the Phagocytic Clearance in the Alzheimer's Brain

Tsuneya Ikezu, MD, PhD
Boston University (Boston, MA)
Year Awarded:
2016
Grant Duration:
July 1, 2016 to June 30, 2020
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2016551S
Award Type:
Standard
Award Region:
US Northeastern
Tsuneya Ikezu, MD, PhD

Novel TREM2 Reporter Platform for Drug Discovery

Summary

We propose to identify a drug, which can enhance clearance of unwanted protein buildup, consisting of degraded nerve fibers (called fibrils) and dead cells, in the Alzheimer’s disease (AD) brain. For that purpose, we will focus on a new molecule, triggering receptor expressed on myeloid cells 2 (TREM2), which has never been tested for the development of a drug. The molecule is expressed on the surface of brain immune cells and facilitates their uptake of protein fibrils and dead cells. We will validate the candidate drugs on tissue-cultured cells from humans, and on animal models of AD. Our long-term goal is to discover a prophylactic and therapeutic drug for the treatment of AD. 

Details

We are interested in developing drug candidates for the treatment of Alzheimer's disease (AD) by targeting a new molecular target, called TREM2 [triggering receptor expressed on myeloid cells 2] and its activating molecule, TYROBP [TYRO protein tyrosine kinase-binding protein]. TREM2 is mostly expressed in macrophages in the body and brain, and mediates scavenging of dead cells and immune activation. Mutations in these genes are known to cause Hasu-Hakola disease, a detrimental neurodegenerative disorder with significant chronic inflammation. A rare point mutation in TREM2 gene was recently found to be highly associated with late-onset AD. To identify a new drug to target this signaling, we have created a drug screening platform, which can monitor the interaction of TREM2 and TYROBP in live cells. Using this platform, we will validate pre-screened drug candidates. We will also test whether the select drugs can slow the Alzheimer-like pathology in animal models, and validate the therapeutic effect in human blood-derived monocytes. Our long-term goal is to develop preventive or therapeutic drugs for AD.

About the Researcher

Tsuneya Ikezu is a professor of pharmacology and neurology at Boston University School of Medicine. Dr. Ikezu received his MD and PhD degrees from University of Tokyo School of Medicine (Japan), and completed post-doctoral training at Massachusetts General Hospital and Cleveland Clinic Foundation. He has been investigating Alzheimer’s disease (AD) over 20 years, and he has performed pioneering research into how modulation of neuroinflammation or neurogenesis enhances hippocampal function and ameliorates AD-like neuropathology through viral gene transfer system. He originally discovered caveolae as a platform of APP processing, cloned tau-tubulin kinase-1 as a neuron-specific tau kinase, characterized anti-inflammatory cytokine modulation of hippocampal neurogenesis for cognitive enhancement, described microglia-neural stem cell interactions, and recently discovered new roles of microglia and exosomes for spreading of pathogenic tau protein in the brain. He has authored more than 70 journal articles, edited the textbook, “Neuroimmune Pharmacology” as a senior editor, and served on the editorial boards of Journal of Neuroimmune Pharmacology, Archivum Immunologiae et Therapiae Experimentalis, and PLoS One [Public Library of Science One]. Over his career, Dr. Ikezu has served on multiple NIH study sections and received the Vada Kinman Oldfield Alzheimer’s Research Award in 2000 and the Inge Grundke-Iqbal Award for Alzheimer's Research in 2016.

Personal Story

Life is short. People age without exception. So the question becomes one of how to sustain the quality of life when you get aged? Alzheimer's disease (AD) is the most dominant senile brain disorder without cure, and captured my interest at the beginning of my research career. I thought perhaps I can contribute a little to move the science forward.

After more than 20 years of research, we learned a lot about this devastating disease and there are many interesting molecules for therapeutic targeting. TREM2 [triggering receptor expressed on myeloid cells 2] is a newly discovered AD gene and is a very interesting molecule, since it will bridge innate immune cells of the body and mind (macrophages and microglia, among others) to fight the disease. Its role in AD, however, is poorly understood. This motivated us to develop a new drug screening tool to monitor the interaction of TREM2 and its adapter molecule, TYROBP, in real-time manner.

My research team is very appreciative of this funding from BrightFocus foundation to explore the therapeutic potential of this under-explored molecule through our robust drug screening in cell and animal models. Since TREM2 is also associated with Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis, targeting this molecule may have a broader impact.

Publications

Muraoka S, Lin W, Chen M, Hersh SW, Emili A, Xia W, Ikezu T. Assessment of separation methods for extracellular vesicles from human and mouse brain tissues and human cerebrospinal fluids. Methods. 2020 Feb 5. pii: S1046-2023(20)30030-X. doi: 10.1016/j.ymeth.2020.02.002. [Epub ahead of print] PubMed PMID: 32035230. PubMed Icon Google Scholar Icon <

You Y, Botros MB, Enoo AV, Bockmiller A, Herron S, Delpech JC, Ikezu T. Cre-inducible Adeno Associated Virus-mediated Expression of P301L Mutant Tau Causes Motor Deficits and Neuronal Degeneration in the Substantia Nigra. Neuroscience. 2019 Nov 2. pii: S0306-4522(19)30687-6. doi: 10.1016/j.neuroscience.2019.10.001. [Epub ahead of print] PubMed PMID: 31689387. PubMed Icon Google Scholar Icon

You Y, Ikezu T. Emerging roles of extracellular vesicles in neurodegenerative disorders. Neurobiol Dis. 2019 Jun 20:104512. doi: 10.1016/j.nbd.2019.104512. [Epub ahead of print] Review. PubMed PMID: 31229685. PubMed Icon Google Scholar Icon

Delpech JC, Herron S, Botros MB, Ikezu T. Neuroimmune Crosstalk through Extracellular Vesicles in Health and Disease. Trends Neurosci. 2019 Mar 26. pii: S0166-2236(19)30024-4. doi: 10.1016/j.tins.2019.02.007. [Epub ahead of print] Review. PubMed PMID: 30926143. PubMed Icon Google Scholar Icon

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