Researchers at the Hong Kong University of Science and Technology (HKUST) have identified new therapeutic targets for Alzheimer's disease by studying the patients' brain with a newly-developed methodology; opening up potential for new Alzheimer’s Disease drug development.
Alzheimer’s Disease, the most common form of dementia, currently affects over 50 million individuals worldwide and is projected to afflict 150 million people by 2050. Its pathological hallmarks include the accumulation of extracellular amyloid-beta depositions and neurofibrillary tangles. Over time, ineffective clearance of these pathological hallmarks leads to cellular dysfunction in Alzheimer’s Disease, resulting in memory loss, communication problems, reduced physical abilities, and eventually death.
Although the pathological mechanisms of Alzheimer’s Disease have been studied for decades, the disease remains incurable. One reason is that conventional research approaches have limited capability to identify molecular targets for drug development. Molecular and pathological pathway analysis generally examines Alzheimer’s Disease patients' brain as a single unit, which usually underestimates the contributions of different brain cell types to Alzheimer’s Disease and any abnormalities in them. This is especially the case with less-common cell types such as microglia (the brain's resident immune cells) and neurovascular cells (specifically endothelial cells), which only account for less than 5 percent and 1 percent of the total brain cell population, respectively.
However, a team led by Professor Nancy Ip, Vice-President for Research and Development, Director of the State Key Laboratory of Molecular Neuroscience, and Morningside Professor of Life Science at HKUST, has more than circumvented this problem. The team was able to identify several new potential molecular targets in endothelial cells and microglia for Alzheimer’s Disease drug development.
The team examined the functions of specific cell types in the post-mortem brains of Alzheimer’s Disease patients, which is typically impossible with conventional approaches, by using cutting-edge, single-cell transcriptome analysis, which can be used to characterize of the molecular changes in single cells. This yielded a comprehensive profile of the cell-type-specific changes in the transcriptome in the brains of Alzheimer’s Disease patients. Subsequent analysis identified cell subtypes and pathological pathways associated with Alzheimer’s Disease, highlighting a specific subpopulation of endothelial cells found in the brains' blood vessels. Accordingly, the team discovered that increased a formation of new blood vessels from current ones and immune system activation in a subpopulation of endothelial cells are associated with the pathogenesis of Alzheimer’s Disease, suggesting a link between the malfunction of blood vessels and Alzheimer’s Disease. The researchers also identified novel targets for restoring neural homeostasis in Alzheimer’s Disease patients.
The team leveraged on their single-cell transcriptome analysis to study the mechanism by which the cytokine interleukin-33 (IL-33), an important protein for immune signalling, exerts beneficial actions, making it a possible Alzheimer’s Disease therapeutic intervention. The researchers found that IL-33 reduces Alzheimer’s Disease pathophysiology by stimulating the development of a specific subtype of microglia that helps clear amyloid-beta, a neurotoxic protein found in Alzheimer’s Disease brains. The research team is also the first to capture data on the mechanisms by which microglia transform into an amyloid-beta-consuming phagocytic state, which is a major cellular mechanism for the removal of pathogens.
“The complex and heterogeneous cell composition within the brain makes it difficult to study disease mechanisms. The advancement of single-cell technology has enabled us to identify specific cell subtypes and molecular targets, which is critical for developing new interventions for Alzheimer's disease,” said Professor Ip.
The team has recently published their work in the prestigious scientific journals Proceedings of the National Academy of Sciences (PNAS) and Cell Reports.