In Situ Tissue Labeling of Cerebral Amyloid Using HIV-Related Tat Peptide

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)6834-6840
Number of pages7
JournalMolecular Neurobiology
Volume55
Issue number8
DOIs
Publication statusPublished - Aug 1 2018

Fingerprint

Amyloid Plaques
Amyloid
HIV
Alzheimer Disease
Brain
Amyloidosis
Peptides
Immunoglobulin lambda-Chains
Gerstmann-Straussler-Scheinker Disease
Cell-Penetrating Peptides
Fixatives
Protamines
Trans-Activators
Heparitin Sulfate
Blood-Brain Barrier
Formaldehyde
Lysine
Arginine
Dementia
Protein Domains

Keywords

  • Cerebral amyloid
  • HIV-related TAT
  • In situ labeling
  • Peptide

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

In Situ Tissue Labeling of Cerebral Amyloid Using HIV-Related Tat Peptide. / Maderna, E.; Colombo, L.; Cagnotto, A.; Di Fede, G.; Indaco, A.; Tagliavini, F.; Salmona, M.; Giaccone, G.

In: Molecular Neurobiology, Vol. 55, No. 8, 01.08.2018, p. 6834-6840.

Research output: Contribution to journalArticle

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