Alzheimer risk genes converge on microglia
March 18, 2020
Science Daily/VIB (the Flanders Institute for Biotechnology)
Our DNA determines a large part of our risk for Alzheimer's disease, but it remained unclear how many genetic risk factors contribute to disease. A team led by Prof. Bart De Strooper (VIB-KU Leuven) and Dr. Mark Fiers now show that many of risk factors affect brain maintenance cells called microglia, and more particularly their response to amyloid-beta, one of the proteins aggregating in the brains of Alzheimer patients. The individual effects of small genetic variations are likely small, but the combination of hundreds of such subtle alterations might tip the balance and cause disease.
Why do some people get Alzheimer's disease while others do not, even when growing very old? Despite decades of research, we still don't know the full answer to this question. Epidemiological studies show that about two-thirds of a person's risk for Alzheimer's disease is genetically determined. A few dozen risk genes have been identified, however, recent evidence shows that there could be hundreds of additional genetic variants that each contribute in a small but significant way to disease risk.
From risk gene to disease mechanism
Bart De Strooper (VIB-KU Leuven) has been studying the mechanisms of Alzheimer's disease for decades. His team tries to find out what this combined genetic risk can teach us about how the disease develops in our brain: "Two crucial questions arise from the myriad of genetic studies. First, what is the link between these Alzheimer risk genes and the amyloid-beta plaques or tau tangles we find in Alzheimer brains; and second, are they all involved in one central cellular or molecular pathway, or do they define many parallel pathways that all lead to Alzheimer's?"
The researchers set out to understand when these genes are expressed and in particular, whether they respond to tau or amyloid?beta pathology. "When it comes to risk, you always need to take the context into account," explain Mark Fiers, co-lead author of the study. "If you don't wear your seatbelt in the car, there is no problem as long as you don't have an accident."
With this in mind, the researchers aimed to understand under which circumstances genetic risk for Alzheimer's comes into play. Fiers: "Almost every person develops some degree of Alzheimer pathology in the brain, i.e. amyloid-beta plaques and tau tangles. However, some people remain cognitively healthy despite a high pathology load, while others develop Alzheimer symptoms quite rapidly."
"To gain more insight we checked gene expression in two different mouse models of Alzheimer's, one displaying amyloid-beta and the other tau pathology, at different ages," says Annerieke Sierksma, a postdoctoral researcher in De Strooper's lab. "We identified that many of the genes linked to Alzheimer's risk are particularly responsive to amyloid-beta but not to tau pathology."
Microglia activation
The team identified 11 new risk genes that are significantly upregulated when facing increased amyloid-beta levels. All these genes are expressed in microglia, cells that play a key role in brain maintenance.
Ashley Lu, a PhD student closely involved in the analysis: "We could confirm that microglia exposed to amyloid-beta drastically switch to an activated status, something that occurs to a much lesser extent in the tau mice. These new insights indicate that a large part of the genetic risk of Alzheimer's disease involves the microglial response to amyloid-beta."
Understanding genetic risk
Should we rethink the classical gene?based view, where certain mutations or genetic variants lead to disease? De Strooper thinks so: "One single genetic variant within a functional network will not lead to disease. However, multiple variants within the same network may tip the balance to a disease?causing disturbance. Such a hypothesis could also explain the conundrum that some /individuals with a lot of amyloid-beta in their brain do not develop clinical symptoms."
"While amyloid-beta might be the trigger of the disease, it is the genetic make?up of the microglia, and possibly other cell types, which determines whether a pathological response is induced," adds Fiers. "Identifying which genetic variants are crucial to such network disturbances and how they lead to altered gene expression will be the next big challenge."
Why mice?
"Profiling of postmortem brain tissue only provides insights into the advanced stages of the disease and does not allow to delineate cause-consequence relationships," explains De Strooper. "Genetically modified mouse models on the other hand only partially recapitulate the disease, but they allow for detailed insights into the initial steps of disease, which is of high relevance for preventative therapeutic interventions."
https://www.sciencedaily.com/releases/2020/03/200318104501.htm
How a protein in your brain could protect against Alzheimer's disease
New research sets the stage for new therapeutic strategies for Alzheimer's disease
December 13, 2019
University of Alberta
Research shows that white blood cells in the human brain are regulated by a protein called CD33--a finding with important implications in the fight against Alzheimer's disease, according to a new study.
"Immune cells in the brain, called microglia, play a critical role in Alzheimer's disease," explained Matthew Macauley, assistant professor in theDepartment of Chemistry and co-author on the paper. "They can be harmful or protective. Swaying microglia from a harmful to protective state could be the key to treating the disease."
Scientists have identified the CD33 protein as a factor that may decrease a person's likelihood of Alzheimer's disease. Less than 10 percent of the population have a version of CD33 that makes them less likely to get Alzheimer's disease. "The fact that CD33 is found on microglia suggests that immune cells can protect the brain from Alzheimer's disease under the right circumstances," said Abhishek Bhattacherjee, first author and postdoctoral fellow in the Macauley lab.
Now, Macauley's research shows that the most common type of CD33 protein plays a crucial role in modulating the function of microglia.
"These findings set the stage for future testing of a causal relationship between CD33 and Alzheimer's Disease, as well as testing therapeutic strategies to sway microglia from harmful to protecting against the disease -- by targeting CD33," said Macauley. "Microglia have the potential to 'clean up' the neurodegenerative plaques, through a process called phagocytosis -- so a therapy to harness this ability to slow down or reverse Alzheimer's disease can be envisioned."
Macauley is an investigator with GlycoNet, a Canada-wide network of researchers based at the University of Alberta that is working to further our understanding of biological roles for sugars. GlycoNet provided key funding to get this project off the ground in the Macauley lab and continues to support the ongoing applications of the project.
According to the Alzheimer's Association, 747,000 Canadians are currently living with Alzheimer's or another form of dementia. The disease affects more than 44 million people around the world.
https://www.sciencedaily.com/releases/2019/12/191213124921.htm
Link between brain immune cells and Alzheimer's disease development identified
Absence of microglia prevents plaque formation
August 21, 2019
Science Daily/University of California - Irvine
Scientists from the University of California, Irvine School of Biological Sciences have discovered how to forestall Alzheimer's disease in a laboratory setting, a finding that could one day help in devising targeted drugs that prevent it.
The researchers found that by removing brain immune cells known as microglia from rodent models of Alzheimer's disease, beta-amyloid plaques -- the hallmark pathology of AD -- never formed. Their study will appear Aug. 21 in the journal Nature Communications.
Previous research has shown most Alzheimer's risk genes are turned on in microglia, suggesting these cells play a role in the disease. "However, we hadn't understood exactly what the microglia are doing and whether they are significant in the initial Alzheimer's process," said Kim Green, associate professor of neurobiology & behavior. "We decided to examine this issue by looking at what would happen in their absence."
The researchers used a drug that blocks microglia signaling that is necessary for their survival. Green and his lab have previously shown that blocking this signaling effectively eliminates these immune cells from the brain. "What was striking about these studies is we found that in areas without microglia, plaques didn't form," Green said. "However, in places where microglia survived, plaques did develop. You don't have Alzheimer's without plaques, and we now know microglia are a necessary component in the development of Alzheimer's."
The scientists also discovered that when plaques are present, microglia perceive them as harmful and attack them. However, the attack also switches off genes in neurons needed for normal brain functioning. "This finding underlines the crucial role of these brain immune cells in the development and progression of Alzheimer's," said Green.
Professor Green and colleagues say their discovery holds promise for creating future drugs that prevent the disease. "We are not proposing to remove all microglia from the brain," Professor Green said, noting the importance of microglia in regulating other brain functions. "What could be possible is devising therapeutics that affect microglia in targeted ways."
He also believes the project's research approach offers an avenue for better understanding other brain disorders.
"These immune cells are involved in every neurological disease and even in brain injury," Professor Green said. "Removing microglia could enable researchers working in those areas to determine the cells' role and whether targeting microglia could be a potential treatment."
https://www.sciencedaily.com/releases/2019/08/190821082236.htm