Dr. Kipnis’ team is focusing on their newly discovered brain-meninges barrier structures known as arachnoid cuff exit (ACE) points. As blood vessels exit the brain through the protective meningeal barrier, they create small gaps—ACE points—between themselves and the barrier. These ACE points allow CSF and any waste or brain molecules collected to exit the brain. ACE points also allow limited entry of molecules and immune cells into the brain. A growing body of data suggests that changes in CSF flow rates are associated with Alzheimer’s disease and that reduced flow may contribute to amyloid beta buildup in the brain by preventing normal drainage. Understanding the cells or other mechanisms that control these border gates—or identifying ways to enhance CSF flow through them—can then be explored in future projects for potential therapeutic interventions.
The team proposed that mast immune cells regulate the flow of CSF through ACE points via dilation of the blood vessels that the cuffs surround. Increasing the vessel size constricts the available space for CSF to flow around the vessel inside the cuff, whereas decreasing it creates more room. The Kipnis team is focusing on mast cells because they reside in the meninges and produce histamine, which regulates blood vessel dilation. Mast cells are also implicated in migraines, which have been linked to AD risk in recent studies. The team is testing the hypothesis that mast cells contribute to amyloid buildup by blocking normal CSF flow. They proposed three experimental aims. In the first aim, they are determining if ACE points are controlled by meningeal mast cells in normal healthy mice. In the second aim, they are testing if these mast cells contribute to amyloid pathology in 5xFAD mice, and in their third aim, they are determining whether amyloid pathology is associated with ACE points and mast cells in autopsied human brain tissue donated from Alzheimer’s patients.
At the close of the first year of funding, the team confirmed that meningeal mast cells play a key role in regulating CSF flow through ACE points by releasing histamine, which dilates blood vessels and impairs CSF flow. They also uncovered a potential link between the scalp microbiome and AD pathology, showing that microbial peptides can activate mast cells, contributing to amyloid buildup in 5xFAD mice. Finally, an early analysis of post-mortem human meningeal tissue points to mast cell alterations in AD patients. Moving forward, they will continue to investigate mast cell depletion in disease progression, explore the scalp microbiome as a therapeutic target, and expand human tissue studies to establish links between mast cells, ACE points, and AD.
