Using CAR macrophages to target and resorb amyloid plaques in Alzheimer’s Disease

Alzheimer’s disease is a devastating condition, and while we don’t fully understand it, we know that sticky clumps of a protein called beta-amyloid (Aβ) build up in the brain, forming “plaques.” Recent antibody treatments have shown that reducing these plaques can help slow down memory decline in early AD, but they can also have side effects.

This paper explores a new, innovative approach: using specially engineered immune cells, called CAR-macrophages (CAR-Ms), as a “living drug” to target and clear these Aβ plaques.

What We Did: Engineering Macrophages for Alzheimer’s

  1. The “Smart” Macrophages: We took macrophages (a type of immune cell that acts like a garbage collector) and gave them a special “Chimeric Antigen Receptor” (CAR). This CAR acts like a highly specific antenna, allowing the macrophages to recognize and grab onto Aβ, similar to how we have engineered them to fight cancer cells. We used a part of an FDA-approved AD antibody (aducanumab) to make sure our CAR-Ms specifically targeted Aβ.
  2. First Try – Not Quite There: When we injected these first-generation CAR-Ms directly into the brains of mice with AD-like plaques, they found the plaques and started to interact with them. However, they didn’t stick around long enough and couldn’t significantly reduce the plaque burden. It was like sending a cleanup crew that quickly ran out of steam.
  3. The “Reinforced” Upgrade: To solve the persistence problem, we engineered a “next-generation” CAR-M. These “reinforced CAR-Ms” were designed to secrete their own growth factor, called M-CSF. This is like giving our cleanup crew their own self-sustaining food supply, allowing them to survive and even multiply in the brain without needing extra help.
  4. Clearing the Path: Before injecting the reinforced CAR-Ms, we gave the mice a drug (PLX5622) that temporarily reduces the brain’s own resident immune cells (microglia). This was to make more room for our engineered CAR-Ms to settle in and do their job.

What We Found: A Powerful Cleanup Crew

  1. Better Survival and Expansion: The reinforced CAR-Ms survived much better and even expanded significantly in the mouse brains compared to the first-generation cells. They truly became a self-maintaining cleanup crew.
  2. Plaque Reduction! Crucially, these reinforced CAR-Ms significantly reduced the amount of Aβ plaques in the hippocampus (a brain region vital for memory) of the AD mice. This was a local effect, meaning they cleaned up plaques right where they were injected.
  3. Efficient Degradation: Not only did these CAR-Ms pick up more Aβ, but they also broke it down much faster inside the cell than regular macrophages. This is important because it means they’re actually getting rid of the harmful protein, not just moving it around.
  4. Targeting All Plaques: The CAR-Ms were effective at clearing plaques of all sizes, and they seemed particularly good at tackling larger plaques.

Why This Matters for Alzheimer’s

  • A New Therapeutic Platform: This research shows that CAR-Ms could be a powerful new “living drug” platform for treating diseases like AD, where harmful substances accumulate over time. To make this more effective, these would need to be delivered systemically, and infiltrate the entire brain – topics we are currently studying.
  • Beyond Cancer: It expands the potential of CAR cell therapy beyond its current use in cancer, opening doors for treating other complex diseases.
  • Overcoming Limitations: By engineering cells to be self-sustaining (like our “reinforced” CAR-Ms), we can overcome challenges like poor cell survival in difficult environments like the brain.
  • Potential for Fewer Side Effects: Unlike some antibody treatments that can cause side effects by accumulating amyloid-antibody complexes, CAR-Ms might offer a cleaner way to remove plaques by degrading them directly.

Future Directions

While promising, this is just the beginning. Future research will focus on:

  • Making CAR-Ms spread throughout the entire brain more effectively.
  • Finding ways for CAR-Ms to be delivered less invasively (e.g., through the bloodstream).
  • Understanding why these CAR-Ms don’t persist long-term in the brain, and whether long-term persistence is even desirable for a therapeutic approach.
  • Targeting other pathogenic material in addition to amyloid.

In essence, this study demonstrates a new approach to treating Alzheimer’s by arming the body’s own cleanup cells with a precise targeting system, offering a new hope for tackling this challenging disease.

Reference: https://insight.jci.org/articles/view/175015

This project, led by MD/PhD graduate student Alex Kim, was a productive and fun collaboration with the research teams of Dr. Jin-Moo Lee and Dr. Abhinav Diwan.