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Alzheimer'sNeurology

Alzheimer’s Disease: The Fault in Our Astrocytes

BY

– MD Student

Affiliations : The Unviersity of Western Ontario, London, Canada

Journal reference: doi: 10.1038/s41593-020-0624-8

Summary: Our brains have a multitude of cells called glia that support neurons. In “Alzheimer’s Disease: The Fault in Our Astrocytes ” Dr. Sawaya focuses on the role a particular kind of glia – astrocytes – play in the development of Alzheimer’s Disease.

Some background on Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative condition that affects nearly 50 million people around the world, increasing dramatically over the past 30 years. People afflicted with the disease notoriously experience worsening memory impairment, and other cognitive dysfunctions as the malady progresses. This makes AD a particularly harrowing condition, stripping individuals of their sense of self and of their orientation in the world.

Unfortunately, the mechanisms behind AD remain poorly understood. Though neuroscientists have long understood that it results from the accumulation of beta-amyloid plaques in the brain, killing neurons in critical regions, the factors that lead to the buildup of plaques are  still elusive. This makes tackling AD difficult as there are currently no disease-modifying treatments, and clinical trials for new pharmacological agents are seldom successful. 

Historically, most groups studying AD have focused on neurons, the well-known brain cells that use electrical signals to transmit signals to and from the brain. However, there is now an increasing amount of interest aimed at other cells found in brain tissue: glia. Glia are a family of non-neuronal brain cells that support and protect neurons. Astrocytes are the most common glia, and may help us further understand the pathological processes responsible for AD. 

Experiments investigating the role of astrocytes in AD

In this new study published in Nature Neuroscience by Naomi Habib and colleagues, the team initiated an investigation to characterize astrocytes in mice genetically engineered to develop AD (AD mice). Authors thus retrieved nuclei of cells present in the hippocampus (the memory center of the brain) of AD mice and compared them to those of normal mice.

First, they identified multiple astrocyte profiles, based on their expression of GFAP (glial fibrillary acidic protein), a protein produced by reactive astrocytes in response to stress. AD mice were found to have more GFAP-high astrocytes compared to their normal counterparts, and an additional GFAP-high astrocytes was identified, named disease-associated astrocytes (DAA) by the team.

Second, the team looked to better understand DAAs by examining the genes most active (upregulated) in this cell-type compared to low-GFAP astrocytes. Genes upregulated in high-GFAP astrocytes are known to be involved in cell development, cell metabolism and cell response to inflammation. In addition DAAs expressed genes involved in molecular transport, immune responses and aging. More specifically, DAAs upregulated two genes of interest Serpina3n and Ctsb, both involved in the processing of beta-amyloid plaques.

Third, the team moved on to the end-product of genes: proteins. They attempted to identify DAAs by staining slices of hippocampus for proteins such as GFAP, SERPINA3N and VIM (a protein produced by reactive astrocytes). Based on this technique, they identified DAAs only in AD mice, but not in normal mice. Most importantly, astrocytes positive for both VIM and SERPINA3N were detected next to beta-amyloid plaques and SERPINA3N were found within the plaques, further confirming its association with the disease.

The team then attempted to place DAA in the spectrum of AD disease progression by looking at normal mice at different stages of their lives and compared them to AD mice. Interestingly, AD mice had increased DAAs earlier in life and notably, before any cognitive deficits became apparent, meaning it could help put in place an earlier diagnosis of the disease.

Finally, the team looked for DAA-like cells in the brains of normal mice and humans. In normal mice, DAA-like cells developed with normal aging. In postmortem human brains, DAA-like cells were identified in individuals who had been diagnosed with AD, suggesting that the findings in this study may help in understanding the disease in humans.

Take-home message

In their interpretation, the authors of the study believe that astrocytes play a significant role, in conjunction with neurons, in the development of Alzheimer’s disease. They hypothesized that astrocytes initially react to beta-amyloid with the intention of protecting neurons, but as the disease progresses, they turn destructive, contributing to the disease as DAAs. The hope is that the characterization of DAAs provided by Habib and team can provide other groups with new therapeutic targets. Alzheimer’s disease, like many other conditions, will likely require more than one approach to effectively halt the progression of the disease.

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