A groundbreaking study led by Prof. Dr. Christian Madry at the Institute of Neurophysiology, Charité – Universitätsmedizin Berlin, has identified the protein CLIC1 as a critical regulator in microglia, the brain’s immune cells, with significant implications for Alzheimer’s disease. Published in Science Advances and supported by a €120,000 grant from the Alzheimer Forschung Initiative e.V. (AFI), the research sheds light on how microglia function and offers potential new therapeutic avenues.
Microglia serve as the brain’s guardians and cleanup crew, constantly scanning for pathogens, debris, or harmful deposits using highly mobile extensions. The study reveals that CLIC1 (Chloride Intracellular Channel 1) plays a dual role in these cells. First, it controls the mobility of microglial extensions, enabling efficient surveillance and clearance of toxic amyloid-beta proteins in early Alzheimer’s stages, before they form damaging plaques. Without CLIC1, microglia lose their characteristic branching and ability to monitor brain tissue effectively, impairing their capacity to detect and remove harmful substances.
Second, CLIC1 regulates the release of pro-inflammatory molecules via the NLRP3 inflammasome. While inflammation is typically protective, in Alzheimer’s, overactive microglia release excessive inflammatory substances, contributing to disease progression by damaging neurons. Blocking CLIC1 could reduce this harmful inflammation, potentially slowing the disease in later stages.
The study’s findings were validated using human stem cells and brain tissue obtained ethically during necessary surgeries, confirming their relevance to human biology. This opens two therapeutic possibilities: in early Alzheimer’s, enhancing CLIC1 activity could boost microglia’s ability to clear amyloid-beta, while in later stages, inhibiting CLIC1 could curb destructive inflammation. Notably, CLIC1’s near-exclusive presence in microglia within the human brain makes it an attractive target for therapies with minimal side effects.
The research underscores microglia’s pivotal role in neurological diseases, particularly Alzheimer’s, where their ability to initiate and regulate inflammation is a key factor in disease progression. The team is now developing an Alzheimer’s mouse model lacking CLIC1 to further explore its role across disease stages and is validating findings in human brain tissue to advance toward clinical applications.
