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How do beta-amyloid oligomers affect brain immune cells in Alzheimer’s?
Giulia Albertini, Ph.D.
VIBvzw
Gent, Belgium
Background
Beta-amyloid protein accumulates to form plaques, one of the hallmark brain changes observed in Alzheimer’s. Before it forms plaques, beta-amyloid molecules form smaller clumps known as oligomers. Studies show that beta-amyloid oligomers may be associated with damage to nerve cells in the brain observed in Alzheimer’s. One possible mechanism for how oligomers are associated with nerve cell damage is through another brain cell called microglia. Microglia are the primary immune cells in the brain that serve as one of the first defenses against nerve cell damage. Microglia sense and help remove unwanted proteins from the brain, including beta-amyloid oligomers. However, increased and long-term activation of the microglia can lead to brain inflammation which can lead to damage to nearby nerve cells. However, exactly how these oligomers affect microglia activation and lead to Alzheimer’s is still not well understood.
Research Plan
Dr. Giulia Albertini and colleagues aim to better understand how beta-amyloid oligomers affect microglia, and how these changes in microglia can lead to nerve cell death. The researchers will first look at a specific type of microglia, called “cytokine-response microglia” or CRM. The activation of these microglia could be an early response to beta-amyloid oligomers, which with long-term activation, could lead to brain inflammation Using genetically-engineered mice which contain human microglia, the team will inject beta-amyloid oligomers into the brain’s of the mice and study how the microglia and nerve cells respond over time. The research group will then determine if the changes are due to oligomers directly interacting with the microglia, or due to the oligomers impacting other brain cells, such as nerve cells, which causes a microglia response. They will do this by removing a protein located on the surface of the microglia which can detect beta-amyloid and help the microglia respond.
Further they will determine if microglia are necessary for beta-amyloid oligomers’ to become toxic to nerve cells by removing the microglia from the brains of the mice. Finally, Dr. Albertini and colleagues will test how an antibody (small molecules that bind to proteins to mark them for clearance) which targets beta-amyloid, impacts microglia.
Impact
The results of these studies will confirm how beta-amyloid oligomers affect microglia in the brain and which biological mechanisms can be targeted to alter this effect to possibly prevent or reduce Alzheimer’s symptoms. Further testing will also determine if microglia are required for the effect of beta-amyloid oligomers on nerve cells in the brain, and if antibody treatments have an effect on microglia.
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