%0 Journal Article %J J Alzheimers Dis %D 2020 %T New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AβPPβ Cleavage Decreasing Amyloid-β Production and Accumulation in Alzheimer's Disease Models. %A Resende, Rosa %A Ferreira-Marques, Marisa %A Moreira, Patrícia %A Coimbra, Judite R M %A Baptista, Salete J %A Isidoro, Ciro %A Salvador, Jorge A R %A Dinis, Teresa C P %A Pereira, Cláudia F %A Santos, Armanda E %X

BACKGROUND: A disease-modifying therapy for Alzheimer's disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP 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 AβPP (AβPPswe) 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-retro in verso 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 Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPPβ 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.

%B J Alzheimers Dis %V 76 %P 1317-1337 %8 2020 Aug 18 %G eng %N 4 %R 10.3233/JAD-200381