The new β amyloid-derived peptide Aβ1–6A2V-TAT(D) prevents Aβ oligomer formation and protects transgenic C. elegans from Aβ toxicity

Neurobiology of Disease

Margherita Romeo¹  Fabrizio Tagliavini²  Alessandro Rossi²  Matteo Stravalaci²  Mario Salmona²  Luisa Diomede²  Marten Beeg²  Alfredo Cagnotto²  Giuseppe Di Fede³  Marco Gobbi³ 

[1] Corresponding author.;Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri”, Via La Masa 19, 20156 Milan, Italy;Division of Neurology and Neuropathology, “Carlo Besta” National Neurological Institute, 20133 Milan, Italy;

关键词: Alzheimer's disease;    Amyloid β;    AβA2V;    Oligomer;    C. elegans;   

DOI  :  

来源: DOAJ

【 摘 要 】

One attractive pharmacological strategy for Alzheimer's disease (AD) is to design small peptides to interact with amyloid-β (Aβ) protein reducing its aggregation and toxicity. Starting from clinical observations indicating that patients coding a mutated Aβ variant (AβA2V) in the heterozygous state do not develop AD, we developed AβA2V synthetic peptides, as well as a small peptide homologous to residues 1–6. These hindered the amyloidogenesis of Aβ and its neurotoxicity in vitro, suggesting a basis for the design of a new small peptide in D-isomeric form, linked to the arginine-rich TAT sequence [Aβ1–6A2V-TAT(D)], to allow translocation across biological membranes and the blood–brain barrier. Aβ1–6A2V-TAT(D) was resistant to protease degradation, stable in serum and specifically able to interfere with Aβ aggregation in vitro, reducing the appearance of toxic soluble species and protecting transgenic C. elegans from toxicity related to the muscular expression of human Aβ. These observations offer a proof of concept for future pharmacological studies in mouse models of AD, providing a foundation for the design of AβA2V-based peptidomimetic molecules for therapeutic purposes.

【 授权许可】

Unknown