A Breakthrough Discovery of New Potential Targets for AD Drug Development

Date: November 5, 2020 Cell Reports

Graphical Abstract

Highlights

• IL-33 induces MHC-II-expressing microglia subpopulations in AD
• IL-33-responsive microglia show enhanced Aβ scavenging activity
• Chromatin state controls the transcriptome signature of IL-33-responsive microglia
• IL.33 stimulated microglial Aβ clearance requires PU.1 activity

Researchers at the Hong Kong University of Science and Technology (HKUST) have identified a new therapeutic target for Alzheimer's disease (AD) by using newly developed methods to study the brains of patients. This novel method also enables researchers to measure the effects of potential drugs on AD patients, thereby opening up new directions for AD research and drug development.

AD is the most common form of dementia and is characterized by misfolded β-amyloid (Aβ) peptides and extracellular protein deposition of neurofibrillary tangles containing hyperphosphorylated Tau protein. Despite decades of research on the pathological mechanism of AD, there is still no cure for the disease. One reason is the limited ability of conventional research methods to identify molecular targets for drug development. Molecular and pathological pathway analysis usually examines the brain of AD patients as a whole, which usually underestimates the contribution of different brain cell types to AD and any abnormalities in it. This is especially true for rare cell types such as microglia (resident immune cells in the brain) and neurovascular cells (especially endothelial cells), which account for less than 5% and 1% of the total brain cells, respectively .

However, the team led by the vice president of research and development, the director of the State Key Laboratory of Molecular Neuroscience, and the life science professor of Hong Kong University of Science and Technology Professor Ye Nanqian, can not only solve this problem, but also found some problems. New potential molecular targets in endothelial cells and microglia are used for AD drug development.

The team used cutting-edge single-cell transcriptome analysis to detect the function of specific cell types in the brain of AD patients after death, which is usually not possible with traditional methods, and can be used to characterize molecular changes in single cells. This produces a comprehensive overview of cell type-specific changes in the transcriptome in the brains of AD patients. Subsequent analysis identified cell subtypes and pathological pathways associated with AD, highlighting specific subpopulations of endothelial cells found in cerebral blood vessels. Therefore, the research team found that increased angiogenesis (new blood vessels formed from current blood vessels) and immune system activation in endothelial cell subsets are related to the pathogenesis of AD, suggesting a link between vascular disorders and AD. Researchers have also identified new targets for restoring the neural homeostasis of AD patients (the ability to maintain a relatively stable internal state despite external changes).

The team also used their single-cell transcriptome analysis to study the mechanism by which the cytokine interleukin 33 (IL-33), an important protein used for immune signaling, plays a beneficial role, making it a possible therapeutic intervention for AD . Researchers have found that IL-33 reduces AD-like pathology by stimulating the development of a specific subtype of microglia, which helps clear amyloid beta (a neurotoxic protein found in the AD brain). The team was also the first to capture data on the mechanism by which microglia transform into a phagocytic state that consumes amyloid, which is the main cellular mechanism for pathogen removal.

The work published in the well-known scientific journals "Proceedings of the National Academy of Sciences (PNAS)" and "Cell Reports."

1. Story Source: Lau, S. F., Chen, C., Fu, W. Y., Qu, J. Y., Cheung, T. H., Fu, A. K., & Ip, N. Y. (2020). IL-33-PU. 1 Transcriptome Reprogramming Drives Functional State Transition and Clearance Activity of Microglia in Alzheimer's Disease. Cell Reports, 31(3), 107530. DOI: 10.1016/j.celrep.2020.107530

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