Fighting Alzheimer's by defusing a death receptor

A receptor that incites cell suicide also promotes the accumulation of β-amyloid plaques in Alzheimer's disease (AD), as He et al. show on page 829. In mice prone to the brain buildups, eliminating the receptor cut the number of plaques and spared memory. The results point to new treatments for the incurable disease. As plaques of β-amyloid collect in the brains of AD patients, large numbers of neurons die. Scientists suspect that this devas-tation stems from abnormal processing of APP, which leads to too much β-amyloid, or out-of-control infl ammation—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 infl ammation, 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, infl ammation-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-secre-tase, one of the enzymes that snips APP to make β-amyloid. TNF-α normally spurs β-secre-tase 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. Infl ammation 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. M itochondria malfunction unless they occasionally fuse with each other. Papers by Song et al. (page 749) and Griparic et al. (page 757) now elucidate the protein processing necessary for these mergers and pin down one of the responsible enzymes. A protein matchmaker that promotes mitochondrial unions is OPA1, which is located in the organelle's inner membrane. The protein is faulty in dominant optic atrophy, an inherited form of blindness. OPA1's many varieties—there are eight mRNA splice variants, each of which encodes polypeptides that undergo further processing—fall into two categories: long and short. Yeast …