Designed Cell-Penetrating Peptide Inhibitors of Amyloid-beta Aggregation and Cytotoxicity

• Amyloid proteins and peptides are a major contributing factor to the development of various neurodegenerative disorders, including Alzheimer’s and prion diseases. Previously, a designed cell-penetrating peptide (CPP) comprising a hydrophobic signal sequence followed by a prion protein (PrP)-derived polycationic sequence (PrP23–28: KKRPKP) was shown to have potent anti-prion properties. Here, we extend this approach toward the amyloid-beta (Aβ) peptide amyloid formation, which is associated with Alzheimer’s disease. We characterized the interactions of the CPP with Aβ using complementary in vitro and in silico experiments. We report that the CPP stabilizes Aβ in a non-amyloid state and inhibits Aβ-induced neurotoxicity. Moreover, replacing PrP23–28 with a corresponding segment from Aβ results in a construct with similar CPP functionality and antagonism of Aβ aggregation and neurotoxicity. Our findings reveal a general underlying principle for inhibition of pathogenic protein aggregation that may facilitate the design of CPP-based therapeutics for amyloid diseases.

Subject headings

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Keyword

aggregation

Alzheimer’s disease

amyloid-beta peptide

cell-penetrating peptides

drug design

neurodegeneration

oligomers

prion protein

protein engineering

signal sequence

Biophysics

biofysik

Publication and Content Type

ref (subject category)

art (subject category)