Selective Secretase Targeting for Alzheimer's Disease Therapy

Alzheimers 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-beta (A beta) in the brain, with a length of 42 and 40 amino acids. alpha-secretase cleaves amyloid-beta protein precursor (A beta PP) producing the membrane-bound fragment CTF alpha and the soluble fragment sA beta PP alpha with neuroprotective activity; beta-secretase produces membrane-bound fragment CTF beta and a soluble fragment sA beta PP beta. After alpha-secretase cleavage of A beta PP, gamma-secretase cleaves CTFa to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTF beta is cleaved by gamma-secretase producing AICD as well as A beta in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as alpha-secretase activity enhancers, beta-secretase inhibitors (BACE-1), and gamma-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing A beta 42. 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 A beta production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of A beta production, such as the development of gamma-secretase modulators or alpha-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.

Automated summary

Alzheimer's disease is characterized by cerebral cortex atrophy and accumulation of amyloid plaques. Current focus in treatment lies in reducing A beta production to slow down disease progression.