A FEMTOMOLAR-ACTING NEUROPROTECTIVE PEPTIDE

A novel 14-amino acid peptide, with stress-protein-like sequences, exh ibiting neuroprotection at unprecedented concentrations, is revealed. This peptide prevented neuronal cell death associated with the envelop e protein (GP 120) from HIV, with excitotoxicity (N-methyl d-aspartate ), with the beta amyloid peptide (putative cytotoxin in Alzheimer's di sease), and with tetrodotoxin (electrical blockade). The peptide was d esigned to contain a sequence derived from a new neuroprotective prote in secreted by astroglial cells in the presence of vasoactive intestin al peptide, The neurotrophic protein was isolated by sequential chroma tographic methods combining ion exchange, size separation, and hydroph obic interaction. The protein (mol mass, 14 kD and pI, 8.3+/-0.25) was named activity-dependent neurotrophic factor, as it protected neurons from death associated with electrical blockade. Peptide sequencing le d to the synthesis of the novel 14-amino acid peptide that was homolog ous, but not identical, to an intracellular stress protein, heat shock protein 60. Neutralizing antiserum to heat shock protein 60 produced neuronal cell death that could be prevented by cotreatment with the no vel protein, suggesting the existence of extracellular stress-like pro teins with neuroprotective properties. These studies identify a potent neuroprotective glial protein and an active peptide that provide a ba sis for developing treatments of currently intractable neurodegenerati ve diseases. (J. Clin. Invest. 1996. 97:2299-2307.)