Using large molecules such as proteins for the treatment of neurological disorders is a relatively unexplored idea, owing in part to the problems associated with their delivery to the nervous system. Two recent papers significantly encourage the development of protein-based therapies by highlighting their potential in rodent models of ischaemia and Alzheimer's disease.

In the first paper, Asoh et al. report the construction of a powerful anti-apoptotic protein that can readily enter cells. They engineered the molecule by fusing the protein transduction domain (PTD) of the HIV/Tat protein with a mutant form of Bcl-xL (FNK) that has a more powerful anti-apoptotic effect than the wild-type protein. The authors obtained evidence that this hybrid molecule could enter cultured neurons and protect them from apoptotic stimuli. More importantly, a prospective intraperitoneal injection of PTD-FNK to gerbils prevented neuronal death in the hippocampus after an episode of ischaemia. These results confirm and extend observations published by Cao et al. using wild-type Bcl-xL. It will now be important to test whether a similar beneficial effect can be obtained if PTD-FNK is administered after the ischaemic insult.

In the second paper, Matsuoka et al. explored the possibility that a peripherally administered protein that binds to the β-amyloid peptide (Aβ) can decrease the brain amyloid burden. Inspired by previous observations by DeMattos et al., which showed that the peripheral administration of an Aβ antibody reduces brain Aβ, Matsuoka et al. injected the Aβ-binding protein gelsolin to Aβ-producing mutant mice. They found that this treatment reduced the brain level of Aβ and its accumulation in plaques in young mice, and that the ganglioside GM1 (another large molecule that binds to Aβ) had a similar effect. As the blood–brain barrier is essentially impermeable to both gelsolin and GM1, these molecules probably act as peripheral sinks of Aβ.

The two papers converge on the idea that protein therapeutics might be a promising strategy to treat neurological disorders. Whether such a promise will be fulfilled in the clinical arena is still open to question.