Researchers at the Hong Kong University of Science and Technology (HKUST) have identified new therapeutic targets for Alzheimer’s disease (AD) by studying the patients’ brain with a newly-developed methodology.
AD, the most common cause 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 AD, resulting in memory loss, communication problems, reduced physical abilities, and eventually death.
The pathological mechanisms of AD have been studied for decades; however, the disease remains incurable. This could be attributed to conventional research approaches that have limited capability to identify molecular targets for drug development. Molecular and pathological pathway analysis generally examines AD patients’ brain as a single unit, which usually underestimates the contributions of different brain cell types to AD 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.
A team of researchers led by Prof. 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 worked to circumvent this problem. In a recent study by the team, they have identified several new potential molecular targets in endothelial cells and microglia for AD drug development. This novel approach also enables researchers to measure the effects of potential drugs on AD patients, opening new directions for AD research and drug development.
The team examined the functions of specific cell types in the post-mortem brains of AD patients, which is typically impossible with conventional approaches, by using cutting-edge, single-cell transcriptome analysis, which were used to characterize molecular changes in single cells. Through this approach, the team obtained a comprehensive profile of the 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 a specific subpopulation of endothelial cells found in the brains’ blood vessels.
The team then discovered that increased formation of new blood vessels and immune system activation in a subpopulation of endothelial cells are associated with the pathogenesis of AD, suggesting a link between the dysregulation of blood vessels and AD.
The researchers also identified novel targets for restoring the ability to maintain a relatively stable internal state despite external changes in AD patients. Leveraging on their single-cell transcriptome analysis, the team studied the mechanism by which the cytokine interleukin-33 (IL-33), exerts beneficial actions, making it a possible AD therapeutic intervention. The researchers found that IL-33 reduces AD-like pathology by stimulating the development of a specific subtype of microglia that helps clear amyloid-beta deposits, a neurotoxic protein found in AD brains. The 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.” Professor Ip explained
The team has recently published this discovery in the scientific journals Proceedings of the National Academy of Sciences (PNAS) and Cell Reports. [APBN]