Selective Secretase Targeting for Alzheimer’s Disease Therapy

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 the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes

“…Different BACE-1 inhibitors entered clinical trials because of the excellent results in preclinical studies. However, these trials proved unsuccessful due to the lack of effectiveness, as for the BACE-1 inhibitor Lanabecestat ( Miranda et al, 2021 ), or because of a cognitive worsening in the patients, as in the case of Umibecestat ( Neumann et al, 2018 ). Similarly, γ-secretase inhibitors failed clinical trials because of many side effects ( Miranda et al, 2021 ).…”

“…However, these trials proved unsuccessful due to the lack of effectiveness, as for the BACE-1 inhibitor Lanabecestat ( Miranda et al, 2021 ), or because of a cognitive worsening in the patients, as in the case of Umibecestat ( Neumann et al, 2018 ). Similarly, γ-secretase inhibitors failed clinical trials because of many side effects ( Miranda et al, 2021 ). As alternative approaches, the inhibition of the Aβ aggregation and the destabilization of pre-existing Aβ aggregates have also been considered.…”

Reducing PDK1/Akt Activity: An Effective Therapeutic Target in the Treatment of Alzheimer’s Disease

“…Subsequently, γ-secretase is recruited to cleave CTFβ, resulting in the production of extracellular Aβ peptides ( Figure 2 ). The balance between the elimination and generation of Aβ peptides is known as the amyloidogenic pathway [ 32 , 33 ]. Excessive Aβ production induces synaptic dysfunction, NFT generation, and the eventual death of neurons within AD-related brain regions [ 7 , 34 , 35 ].…”

Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review

“…The γ-secretase modulator tarenflurbil also worsened cognition in patients with mild AD [ 30 ]. Therefore, the role of secretase inhibitors remains under debate [ 144 , 145 ].…”