TAT fusion proteins as innovative treatment strategy in stroke

The delivery of proteins across the blood-brain barrier is severely limited by the proteins' size and biochemical properties. Thus, a large number of peptides have been characterized in recent years that efficaciously prevent neuronal death in vitro, but which may not be applied in vivo, since they are unable to cross cell membrane barriers. In the 1990ies, it had been shown that the HIV TAT protein is able to cross cell membranes even when coupled with larger peptides. Subsequent studies with fusion proteins of the 11-amino acid protein transduction domain of HIV-TAT revealed that TAT fusion proteins may successfully be used for therapeutic purposes in vivo, even when systemically applied. Indeed, intravenous delivery of TAT proteins linked with anti-apoptotic and neurotrophic factors resulted in a rapid and highly efficacious transduction of the brain tissue. When administered after focal cerebral ischemia, intravenous TAT-proteins significantly reduced brain injury, both when applied after severe and mild ischemic insults. These data provided the in vivo evidence of the efficacy of fusion proteins in the ischemic brain, thus raising new hopes that neuroprotection is feasible after stroke.