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Untangling the Twists of Alzheimer’s Plaques

Researchers from Duke-NUS Medical School and Monash University have uncovered the mechanism behind microglial phagocytosis of amyloid proteins, one of the root causes of Alzheimer’s disease.

With over 50 million people worldwide estimated to suffer from dementia in 2020, and these numbers predicted to skyrocket to 152 million by 2050, dementia has become a public health priority requiring urgent action. Amongst the many types of dementia, Alzheimer’s disease is one of the most prevalent forms, distinctive in its association with amyloid plaques that accumulate in the brain.

Under normal circumstances, the microglia, a type of glial cells located in the brain and spinal cord, serve as immune sentinels that remove foreign invaders and maintain brain homeostasis. While they are known to play a crucial role in clearing toxic substances such as amyloid plaques, their exact role in Alzheimer’s disease has remained shrouded in mystery. That is, up until recently.

A team of researchers from Duke-NUS Medical School and Monash University have recently discovered novel gene expression signatures fundamental in microglia’s role in engulfing amyloid proteins in the brain, a process otherwise known as amyloid plaque phagocytosis. This discovery can potentially pave the way for new targets of intervention to tackle Alzheimer’s.

While the team was examining changes in gene expression in specific human brain cells linked to the development of Alzheimer’s disease, they decided to primarily focus on the microglia. Using a stain called methoxy-XO4, they studied microglia that have engulfed amyloid plaques from preclinical models of Alzheimer’s disease to assess its gene expression. They compared these observations with microglia that have not taken up amyloids to identify distinguishing genetic features that allow for its macrophagic capabilities.

“We sought to understand the molecular mechanisms and differences between microglia that were actively engulfing amyloid plaques in Alzheimer’s disease and those that weren’t,” said Associate Professor Enrico Petretto from Duke-NUS’s Cardiovascular and Metabolic Disorders Programme, a co-senior author of the study.

Based on their findings, they concluded that before engulfing amyloids, the microglia exhibited gene expression patterns similar to aged ones that are recognised as dysfunctional and a key player in causing Alzheimer’s. After they have taken up amyloid plaques, they displayed a distinct gene expression signature, partly engendered by a specific gene called Hif1a. This marked alteration, characterised by increased expression of Hif1a, was found to enhance the ability of microglia to devour amyloid proteins. Vice versa, decreasing Hif1a reduces microglia’s macrophagic properties for amyloids.

Unlocking the regulatory potential of Hif1a may also be the key to better understand the role of microglia in discarding obsolete or impaired synapses. Professor Petretto suspects that this initially protective defence mechanism can be disrupted as the disease progresses, thus impacting amyloid plaque phagocytosis.

In a bid to explore novel targets for drug development, the researchers also utilised computational models to forecast molecular networks associated with microglia phagocytosis of proteins. They made a surprising discovery of how the common immunosuppressant rapamycin can inhibit the gene Hif1A from promoting microglia amyloid plaque phagocytosis.

“This relationship between Hif1a and cognitive decline in Alzheimer’s disease is yet to be comprehensively uncovered,” said PhD student Gabriel Chew, who is a co-first author of the paper. “Future work could focus on using gene-editing tool CRISPR to test the impact of manipulating Hif1a on symptom severity and disease progression.” [APBN]

Source: Grubman et al. (2021). Transcriptional signature in microglia associated with Aβ plaque phagocytosis. Nature Communications, 12(1), 1-22.