Different Profiles of Microglial Activation in Alzheimer's disease

What's the science?

Microglia, the immune cells of the brain, may contribute to Alzheimer’s disease by becoming activated in response to brain pathology (also known as neuroinflammation). Currently, whether neuroinflammation is associated with Alzheimer’s progression (harms the brain) or whether it may be protective (helps to “eat” plaques in the brain) is still a matter of debate. This week in BrainHamelin and colleagues used PET imaging to examine how microglial activation in the brain is related to Alzheimer’s disease progression.

How did they do it?

PET imaging was used to measure the uptake of a radiotracer (18F-DPA-714) in the brain binding to activated microglia. A large group of patients with Alzheimer’s disease were scanned twice for activated microglia, once at baseline and once two years later. They were then followed up annually and scanned with MRI to measure brain volume (measure of Alzheimer’s progression) and given annual cognitive tests to assess dementia severity and cognitive function. Based on this, patients were split into “fast and slow decliner” categories. The microglial activation levels over time were also analyzed compared to a control group of healthy participants.

What did they find?

Having a high level of microglial activation at baseline was predictive of being a slow decliner. In patients with a high baseline neuroinflammation, cognitive performance was better and brain volume was more preserved, suggesting that more microglial activation at baseline is protective. At two years follow-up, microglial activation was higher in Alzheimer’s participants but not controls as would be expected. Increased microglial activation over time was related to worsening cognitive scores and brain atrophy, suggesting that it is harmful. However, when they examined neuroinflammation over time at an individual level, they found that those with the highest baseline microglial activation had the lowest increase in microglial activation over time. They concluded that there is a dynamic relationship, whereby neuroinflammation may affect patients differently, depending on their original level of microglial activity. Microglial activation appears to be protective initially, but exacerbates Alzheimer’s disease over time; to a greater extent in those who had low levels of microglial activation to begin with.


What's the impact?

This is the first study to show that neuroinflammation may affect individuals with Alzheimer’s disease differently depending on their baseline level of microglial activity. It shows us that microglial activation may be helpful or harmful depending on the individual and how far their disease has progressed. Understanding the role microglial activation play in Alzheimer’s disease is an essential part of understanding how the disease progresses.

L. Hamelin et al., Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. Brain (2018). Access the original scientific publication here.

Amyloid-β Proteins Differ Between Alzheimer’s Disease Subtypes

What’s the science?

Alzheimer’s disease can be genetically inherited (familial/heritable) or sporadic. A key feature of the disease is the build up of amyloid-β proteins in the brain. A mutant form of amyloid-β is found in heritable Alzheimer’s disease, and is thought to cause the misfolding of normal amyloid-β proteins, leading to a more rapid build up. Recently in PNASCondello and colleagues probed the structure of different conformations or strains of amyloid-β proteins, to see whether they differ between heritable and sporadic Alzheimer’s.

How did they do it?

They performed confocal spectral imaging using three fluorescent dyes that bind to amyloid protein and are sensitive to protein structure in mouse and human brains. Different dyes bind differently to distinct protein conformations. In mice, they combined mutated and non-mutated amyloid-β, to test whether the mutated form could cause protein misfolding.

What did they find?

The heritable and sporadic amyloid-β plaques exhibited different fluorescence intensities after staining with the three dyes, meaning they could be differentiated. The fluorescence emission spectra also differed between disease types, suggesting different protein conformations. In mice, when mutated and non-mutated amyloid-β were mixed, the mutated amyloid-β acted as a template allowing the normal amyloid-β to misfold.


What’s the impact?

This is the first study to use this fluorescence microscopy technique to assess different strains of amyloid-β. The different protein structure in these amyloid-β strains could help to explain differences in the rate of disease progression, for example between familial Alzheimer’s disease compared to sporadic Alzheimer’s disease. Understanding the differences in protein structure between these amyloid strains may help clarify how they cause other proteins to misfold and the disease to spread.

C. Condello et al., Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer’s disease. PNAS. 115(4) (2018).

Access the original scientific publication here.