New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AβPP-β Cleavage Decreasing Amyloid-β Production and Accumulation in Alzheimer’s Disease Models

Article type: Research Article

Authors: Resende, Rosa^{a; b} | Ferreira-Marques, Marisa^{a; c} | Moreira, Patrícia^{a; c} | Coimbra, Judite R.M.^{a; d} | Baptista, Salete J.^{a; e} | Isidoro, Ciro^f | Salvador, Jorge A.R.^{a; d} | Dinis, Teresa C.P.^{a; g} | Pereira, Cláudia F.^{a; h} | Santos, Armanda E.^{a; g; *}

Affiliations: [a] University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Center for Neuroscience and Cell Biology (CNC), Coimbra, Portugal | [b] University of Coimbra, Institute for Interdisciplinary Research (IIIUC), Coimbra, Portugal | [c] University of Coimbra, Faculty of Pharmacy, Laboratory of Pharmacology, Coimbra, Portugal | [d] University of Coimbra, Faculty of Pharmacy, Laboratory of Pharmaceutical Chemistry, Coimbra, Portugal | [e] Chem4Pharma, Coimbra, Portugal | [f] Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Novara, Italy | [g] University of Coimbra, Faculty of Pharmacy, Laboratory of Biochemistry and Biology, Coimbra, Portugal | [h] University of Coimbra, Faculty of Medicine, Institute of Biochemistry, Coimbra, Portugal

Correspondence: [*] Correspondence to: Armanda Emanuela Santos, Faculdade de Farmácia da Universidade de Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal. Tel.: +351 239488456; E-mail: [email protected].

Abstract: 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-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 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 AβPP-β 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.

Keywords: Alzheimer’s disease, amyloid-β, BACE1 inhibitor, chimeric peptide, CHL1, SEZ6

DOI: 10.3233/JAD-200381

Journal: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1317-1337, 2020