Developing β‐secretase inhibitors for treatment of Alzheimer’s disease

Abstract

β-Secretase (memapsin 2; BACE1) is the first protease in the processing of amyloid precursor protein leading to the production of amyloid-β (Aβ) in the brain. It is believed that high levels of brain Aβ are responsible for the pathogenisis of Alzheimer’s disease (AD). Therefore, β-secretase is a major therapeutic target for the development of inhibitor drugs. During the past decade, steady progress has been made in the evolution of β-secretase inhibitors toward better drug properties. Recent inhibitors are potent, selective and have been shown to penetrate the blood-brain barrier to inhibit Aβ level in the brains of experimental animals. Moreover, continuous administration of a β-secretase inhibitor was shown to rescue age-related cognitive decline in transgenic AD mice. A small number of β-secretase inhibitors have also entered early phase clinical trials. These developments offer some optimism for the clinical development of a disease-modifying drug for AD.

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…2a) [43][44][45]. Until recently, it has been considered difficult to develop BACE1 small molecule inhibitors that are selective, potent, and BBB penetrant [46]. Nevertheless, recent advances have been made in the clinic that show promise for small molecule inhibition of BACE1 [47], yet most of these approaches still lack the specificity that an antibody approach will offer.…”

“…Addressing the latter point: if Aβ were to exist in peripheral/central equilibrium, any approach that lowers Aβ in the periphery should subsequently reduce brain Aβ levels. Unfortunately, the BBB is not a generally permeable barrier and many examples abound where peripheral decreases in Aβ do not result in brain levels being decreased, particularly associated with efforts to develop secretase inhibitors [46]. Indeed, as just reviewed, anti-BACE1 antibodies that inhibit BACE1 activity in the periphery do not show the same reduction of Aβ in brain.…”

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…Amyloid-reduction strategies have been developed on the ground of the amyloid-cascade hypothesis that Aβ pathology is the primary neuropathological core, and therefore, interventions to reduce Aβ levels in the brain have become a promising approach in the sAD therapy research. One option is to change the activity of the enzymes involved in the amyloid precursor protein (APP) processing, but the major obstacle of γ-secretase inhibitors is their toxicity, while β-secretase inhibitors seems to be less toxic and effective in reducing the Aβ levels in the brain accompanied by improvement in cognitive decline in transgenic AD mice models (as reviewed by Ghosh et al 2012). A small number of β-secretase inhibitors have entered early phase clinical trials.…”

Medicinal Plants Anti-cholinesterase Activity and the Potential for Alzheimer’s Disease Treatment

“…Hence the thorough search for the most compatible or suitable biomarkers for disease progress. These has made the argument that, a single cure for AD may likely not be found, a popular opinion among scientist [28,29]. These assertions could be by the fact that, the four approved drugs that are currently in use have many side effects [30][31][32].…”