Delivering
peptide-based drugs to the brain is a major challenge because of the existence of the blood-brain barrier (BBB). To overcome this problem,
cell-penetrating peptides derived from
proteins that are able to cross
biological membranes have been used as cell-permeable and brain-penetrant compounds. An example is the
transactivator of transcription
protein transduction domain (Tat) of the human immunodeficiency virus. The basic domain of Tat is formed of
arginine and
lysine amino acid residues. Tat has been used as brain-penetrant carrier also in
therapies for
Alzheimer disease (AD), the most common form of
dementia characterized by extracellular cerebral deposits of
amyloid made up of Aβ
peptide. The aim of our study was to assess whether Tat bind to
amyloid deposits of AD and other
amyloidoses. An in situ labeling using biotinylated Tat 48-57
peptide was employed in the brain tissue with
amyloid deposits made up of Aβ (patients with AD and transgenic AD mice), of
prion protein (patients with
Gerstmann-Straussler-Scheinker disease), and other
amyloidosis, processed by different fixations and pretreatments of histological sections. Our results showed that Tat
peptide binds
amyloid deposits made up of Aβ, PrP, and
immunoglobulin lambda chains in the brain and other tissues processed by alcoholic
fixatives but not in
formalin-fixed tissue. The fact that biotinylated Tat
peptide stains
amyloid of different biochemical composition and the specific charge characteristics of the molecules suggests that Tat may bind to
heparan sulfate glicosaminoglicans, that are present in
amyloid deposits. Inhibition of the binding by Tat pre-incubation with
protamine reinforces this hypothesis. Binding of Tat to
amyloid deposits should be kept in mind in interpreting the results of studies employing this molecule as brain-penetrating compound for the treatment of cerebral
amyloidoses. Our results also suggest that Tat may be helpful for the analysis of the mechanisms of amyloidogenesis, and in particular, the interactions between specific
amyloid peptides and glicosaminoglicans.