2019-265: Engineered Mammalian Animal and Cell Models to Enable the Identification of Molecules That Target Microglia and Myeloid Cell Function

SUMMARY

UCLA researchers in the Department of Psychiatry have developed novel methods to use human genomic DNA context to drive the expression of microglial-expressing Alzheimer’s disease genes in mammalian cells or mammalian animal models. 

BACKGROUND

Microglia are resident innate immune cells in the brain derived from myeloid precursors. Microglia contribute to synaptic plasticity and learning at the resting state, and reactive microglia mediate phagocytic uptake and secretion of inflammatory cytokines in response to injury or neurodegenerative disorders. While short-term microglia activation promotes tissue repair, chronic microglia activation in the case of Alzheimer’s disease may elicit neurotoxicity and contribute to disease pathogenesis. TREM2 is a membrane protein selectively expressed in myeloid cells, including microglia. TREM2 plays a critical role in age-dependent microglial proliferation and survival, as well as proper function of microglia and myeloid cells in the context of age-dependent brain disorders. Recent Genome-Wide Association Studies in Alzheimer’s disease identified genes that significantly modify the risk of late-onset Alzheimer’s disease to have relatively enriched expression in microglia in human and mouse brains. And a number of these microglia-enriched, and Alzheimer’s disease-associated genes also have genetic, physical, or functional interactions with TREM2, and appear to function in a broad TREM2 signaling pathway.

INNOVATION       

Researchers at UCLA have developed two strategies to express microglial-expressing Alzheimer’s disease (ME-AD)-associated genes under human genomic regulation in mammalian cells or mammalian animal models. The mammalian cell models carrying human ME-AD genomic reporters are used to screen for molecules that can modulate the protein or RNA levels of ME-AD genes expressed from the human genomic reporters, and the mammalian animal models are used to test the ability of molecules to modulate the expression of ME-AD RNA or protein that are expressed from these reporters either in the brain (e.g. microglia), or in the periphery cells (e.g. myeloid cells).

POTENTIAL APPLICATIONS:

• The method is generalized to any ME-AD genes that are implicated in the regulation of microglia function and in pathogenesis of AD and related brain disorders that have implicated microglia in their disease etiology
• The method is suitable for identifying molecules that can affect the transcription, RNA splicing, trafficking and stability of ME-AD genes in the proper cell types under baseline conditions, or in a condition of environmental or disease-related challenges
• The method is suitable for high-throughput screening of molecules that either downregulate or upregulate the levels of ME-AD genes in cell models, and low-to medium throughput screen of any molecules that may regulate the expression of ME-AD genes in vivo in intact animals, both in the CNS or in the peripheral tissues

ADVANTAGES:

• Screen and test molecules that can regulate the levels of human microglial-expressing Alzheimer’s disease-associated RNA and protein from human genomic context

DEVELOPMENT-TO-DATE:

Several cell models and animal models are available