Helping Clear Out Amyloid-β

Forty or so different proteins help seal the gaps between cells that line blood vessels in the brain. These so-called tight junctions are one component of the blood-brain barrier that controls which molecules get in and out of the brain.

A new study reports that lowering levels of two of those proteins can help amyloid-β, a protein associated with Alzheimer’s disease, slip through these gaps to diffuse out of the brain and into the blood. The two proteins represent targets for possible Alzheimer’s therapies that could help clear neurotoxic amyloid-β from the brain, the researchers say.

The study describes a potentially exciting novel pathway for amyloid-β’s clearance, says Terrence Town of the University of Southern California, who was not involved in the study. Most previous studies have focused on how amyloid-β is actively transported through endothelial cells lining brain blood vessels and out of the brain, he adds.

The researchers who carried out the new investigation—Matthew Campbell of Trinity College in Dublin and colleagues—wondered whether amyloid-β could instead passively diffuse around the cells, through the tight junctions between individual endothelial cells.

Campbell and colleagues studied mice genetically engineered to produce large amounts of amyloid-β. They injected the animals every three weeks with small interfering RNAs (siRNAs) designed to lower the levels of two tight-junction proteins, claudin-5 and occludin.

About 48 hours after each injection, levels of amyloid-β spiked in the animals’ blood, a sign that the protein was being cleared from their brains (Sci. Adv. 2015, DOI: 10.1126/sciadv.1500472).

Campbell next wants to test the effects of lowering levels of claudin-5 and occludin combined with injection of an antibody for amyloid-β. He thinks the antibody’s ability to bind and sequester amyloid-β in the bloodstream could enhance the protein’s passive clearance from the brain.

Town thinks one hurdle in translating the findings to the clinic is ensuring that increasing the permeability of tight junctions doesn’t lead to serious side effects. “By messing with tight junctions at the blood-brain barrier, other molecules might be adversely affected.”