New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AßPP-ß Cleavage Decreasing Amyloid-ß Production and Accumulation in Alzheimer's Disease Models

A disease-modifying therapy for Alzheimer's disease (AD) is still an unmet clinical need. The formation of amyloid-ß (Aß) requires the initial cleavage of the amyloid-ß protein precursor (AßPP) by BACE1 (beta-site AßPP cleaving enzyme 1), which is a prime therapeutic target for AD. Objective: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment. Methods: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AßPP (AßPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of the blood-brain barrier. Additionally to the chimeric peptide in the L-form, we developed a D-retroinverso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity. Results: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aß40/42 production in Neuro-2a (N2A) cells expressing AßPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aß40/42 levels, as well as brain soluble AßPPß production. Also, a reduction of insoluble Aß was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AßPP-ß cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6). Conclusions: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD.