Novel TREM2 Reporter Platform for Drug Discovery
Principal Investigator
Project Goals
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.
Project Summary
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.
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.
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.
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.
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.
Delpech JC, Pathak D, Varghese M, Kalavai SV, Hays EC, Hof PR, Johnson WE, Ikezu S, Medalla M, Luebke JI, Ikezu T. Wolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice. Sci Transl Med. 2021 Sep 15;13(611):eabe8455. doi: 10.1126/scitranslmed.abe8455. Epub 2021 Sep 15. PMID: 34524859; PMCID: PMC8763211.
Muraoka S, Jedrychowski MP, Yanamandra K, Ikezu S, Gygi SP, Ikezu T. Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer's Disease Patients: A Pilot Study. Cells. 2020 Aug 25;9(9):1959. doi: 10.3390/cells9091959. PMID: 32854315; PMCID: PMC7565882.
Muraoka S, DeLeo AM, Sethi MK, Yukawa-Takamatsu K, Yang Z, Ko J, Hogan JD, Ruan Z, You Y, Wang Y, Medalla M, Ikezu S, Chen M, Xia W, Gorantla S, Gendelman HE, Issadore D, Zaia J, Ikezu T. Proteomic and biological profiling of extracellular vesicles from Alzheimer's disease human brain tissues. Alzheimers Dement. 2020 Jun;16(6):896-907. doi: 10.1002/alz.12089. Epub 2020 Apr 17. PMID: 32301581; PMCID: PMC7293582.
First published on: July 20, 2016
Last modified on: December 27, 2024