Selective Secretase Targeting for Alzheimer’s Disease Therapy

Article type: Review Article

Authors: Miranda, Alvaro^a | Montiel, Enrique^a | Ulrich, Henning^{b; *} | Paz, Cristian^{a; *}

Affiliations: [a] Departamento de Ciencias Básicas, Universidad de La Frontera, Temuco, Chile | [b] Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP, Brazil

Correspondence: [*] Correspondence to: Prof. Henning Ulrich, Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo 05508-000, SP, Brazil. Tel.: +55 11 97277 6344; E-mail: henning@iq.usp.br; Prof. Cristian Paz, Departamento de Ciencias Básicas, Universidad de La Frontera, Av. Francisco Salazar 01145, Casilla 54-D, Código Postal 4811230, Temuco, Chile. Tel.: +56 45 259 2825; E-mail: cristian.paz@ufrontera.cl.

Abstract: Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Keywords: Alzheimer disease, α-secretase enhancers, β-secretase inhibitors, clinical trials, γ-secretase modulators

DOI: 10.3233/JAD-201027

Journal: Journal of Alzheimer's Disease, vol. 81, no. 1, pp. 1-17, 2021