We went on a lab tour with Dr. Macauley!

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Researchers at the University of Alberta, led by Dr. Matthew Macauley, have uncovered a fascinating link between a protein receptor and Alzheimer's disease. Their study focuses on CD33, a carbohydrate-binding receptor found on immune cells in the brain called microglia. Microglia play a crucial role in brain health, and Dr. Macauley's team discovered two distinct forms of CD33 with opposing effects on these cells.

One form of CD33 acts like a brake, inhibiting microglial function. The other, shorter version accelerates microglia's ability to clear harmful protein plaques associated with Alzheimer's. Interestingly, Dr. Macauley's research suggests a connection between the shorter CD33 form and a lower risk of developing Alzheimer's disease. Here's what we learned.

The Short Summary:

The brain has immune cells called microglia. Microglia attack and remove dangerous accumulations of waste in the brain, but they can cause inflammation when they do so. Overactive microglia can be dangerous in a healthy brain because the inflammation they cause can be destructive. To manage microglia, the body produces a protein called CD33. CD33 is a braking system for microglia, slowing them down when they become overactive.

 In brains with Alzheimer’s and other dementias, we suspect that the CD33 is slowing down the microglia too much, preventing them from doing their job and clearing away dangerous plaques. We also suspect that there are different sub-varieties of CD33. People with some varieties are less likely to get Alzheimer’s because their version of CD33 is good at managing the microglia effectively. In contrast, other people have less effective CD33 and are, therefore, more likely to suffer from Alzheimer’s disease.

 We are now working to learn how exactly CD33 controls the microglia and what varieties of CD33 are the most effective at managing the balance between over- and underactive microglia.

The Longer Summary:

CD33 is a glycoprotein found on the surface of microglia (the primary immune cells in the brain). Its role in dementia, particularly Alzheimer's disease, is tied to how microglia manage and respond to amyloid-beta plaques, a hallmark of Alzheimer's. The relationship between CD33 and microglial function in dementia can be seen in many ways: 

1. Microglial Activation: CD33 impacts the activity of microglia. Normally, CD33 can act as a brake on microglia, helping to prevent overactivation and damaging inflammation. This slowing function is crucial because active microglia can clear plaques and release inflammatory molecules that might harm brain cells. 

2. Clearance of Amyloid-Beta: One of the main jobs of microglia in the brain is to clear out harmful buildup, including amyloid-beta plaques. Research suggests that CD33 can affect this process, with some genetic variants of CD33 linked to more efficient clearance of these plaques. This implies that the presence or absence of certain CD33 variants can influence the risk and progression of dementia.

 3. Inflammation Control: Besides plaque clearance, microglia also help control inflammation within the brain. CD33 plays a part in balancing this inflammation. By controlling how active microglia are, CD33 indirectly influences the level of inflammatory molecules in the brain, which is a critical factor in the progression of neurodegenerative diseases. 

4. Genetic Risk Factors: Variants in the CD33 gene have been associated with increased or decreased risk of Alzheimer's disease. This genetic link underscores the importance of CD33 in the disease's physical mechanisms. Specifically, variants that reduce CD33 activity or expression tend to be associated with a decreased risk of Alzheimer's, likely due to enhanced removal of amyloid-beta by microglia. 

5. Treatment Implications: Given its central role in microglial function and inflammation, CD33 is being explored as a potential target for Alzheimer's therapy. The idea is that by controlling CD33 activity, it might be possible to enhance microglial clearance of amyloid-beta plaques and reduce harmful inflammation, potentially slowing the progression of dementia. 

In essence, CD33's role in dementia revolves around its capacity to regulate microglial functions critical for responding to and managing amyloid-beta plaques in the brain. Its influence on microglial activation, plaque clearance, and inflammation makes it a key player in the development of Alzheimer's disease and a promising target for therapeutic strategies aiming to combat neurodegenerative diseases.