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

Background: A disease-modifying therapy for Alzheimer's disease (AD) is still an unmet clinical need. The formation of amyloid-beta (A beta) requires the initial cleavage of the amyloid-beta protein precursor (A beta PP) by BACE1 (beta-site A beta PP 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 A beta PP (A beta PPswe) 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 AP(40/42) production in Neuro2a (N2A) cells expressing A beta PPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain A beta(40/42 )levels, as well as brain soluble A beta PP beta production. Also, a reduction of insoluble Ap was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the A beta PP-beta 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 peptides hold promising potential as a selective disease-modifying therapy for AD.