β-amyloid (green) clumps in the blood vessels of control mice (above), but the vessels of rodents lacking TNFR1 are clear (below).
As plaques of β-amyloid collect in the brains of AD patients, large numbers of neurons die. Scientists suspect that this devastation stems from abnormal processing of APP, which leads to too much β-amyloid, or out-of-control inflammation—or a combination of the two.
A potential link between these two mechanisms is the tumor necrosis factor type 1 death receptor (TNFR1), which triggers brain cells to kill themselves. TNF-α, which is activated during brain inflammation, switches on the receptor. Three years ago, the researchers showed that β-amyloid could also stimulate TNFR1. He et al. wanted to determine whether TNFR1 affects plaque accumulation and APP processing.
Their subjects were mice that lack TNFR1 and pump out excess APP. Without the receptor, more neurons survived, and the animals carried fewer, smaller plaques. Their brains sported smaller numbers of activated microglia, inflammation-promoting immune cells that are switched on in AD. The rodents also performed better on two memory tests.
Removal of TNFR1 also slashed the amount of β-amyloid the mice fashioned by cutting the amount and activity of β-secretase, one of the enzymes that snips APP to make β-amyloid. TNF-α normally spurs β-secretase production through a pathway that requires NF-κB, the researchers found.
Overall, the study indicates that TNFR1 is pivotal in a destructive positive feedback loop. Inflammation boosts the amount of TNF-α, cranking up the death receptor pathway and producing more β-amyloid, which in turn further stimulates TNFR1. Drugs that block TNFR1 might short-circuit this pathway and save the brain cells of AD patients. 
