Therapeutic targets for alleviating neuroinflammation in Alzheimer Disease

Project Title: Therapeutic targets for alleviating neuroinflammation in Alzheimer disease 

Grant Name: 2022 CLEAR Operating Grant 

Grant Duration: 2022-2024 (two years)

Lay Summary:

Many elderly people don’t have dementia although their brains show changes that are characteristic of Alzheimer disease. Why is this so? It is believed that a key difference between those who suffer from Alzheimer disease and those who don’t is brain inflammation, an idea that will be tested in this research. Stem cell-based approaches will be explored by growing human brain cells in a dish to uncover how and why certain aspects of brain inflammation triggers the changes that occur in Alzheimer disease and how this causes or exacerbates brain damage.

The study will focus on the brain’s immune cells, the microglia, and on a key type of brain support cell, astrocytes. The interactions between these two important brain cell types will be studied in addition to their involvement in brain inflammation using new technologies, including advanced genetic analysis and innovative microscopy approaches. Ultimately, the goal is to be able to identify new therapeutic targets that could dampen or prevent brain inflammation, positively impacting Alzheimer disease.

Research update:

We've made a breakthrough in creating brain cell cultures that mimic what happens in Alzheimer's disease (AD). Our cultures contain three important types of cells found in the brain: neurons, astrocytes, and microglia (Figure 1).

We've been studying how the brain responds to a substance called Aβ, which is linked to AD. In our cultures, Aβ forms clumps similar to what happens in the brains of people with AD. We've seen that after a few weeks of exposure to Aβ, the neurons start to malfunction, leading to their death. We've also looked at how microglia, a type of brain cell, react to Aβ. Surprisingly, we found that they can help protect neurons by clearing away the Aβ and preventing damage.

Now, we're focusing on a protein called PIEZO1, which seems to trigger inflammation in the brain during AD. In our cultures, we've found that PIEZO1 is mainly found in astrocytes and microglia, the same cells where it's seen in AD patients' brains. Our work lays the groundwork for further understanding how Alzheimer's affects the brain and how we might be able to stop it. We've confirmed that our cultures accurately reflect the cell types and gene activity seen in the brain, which is a crucial step forward.

This leads us to asking the most important questions for our second year of the project:

1. How does PIEZO1 expression change after chronic Aβ treatment?
2. What specific roles does glial PIEZO1 expression play in Aβ induced neurotoxicity?
3. Which glial cell type is the principal contributor to Aβ induced toxicity?