Membrane Anchored and Lipid Raft Targeted β-Secretase Inhibitors for Alzheimer's Disease Therapy

Abstract

β-secretase, a key enzyme involved in amyloid-β generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of β-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active β-secretase is sequestered in subcellular compartments, new strategies have to be implemented. We propose that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β-secretase. By choosing cholesterol as a membrane anchor, we also enrich the inhibitor in lipid rafts where much of the β-secretase is present. In addition, membrane-anchoring of soluble inhibitors reduces the dimensionality of the inhibitor and consequently increases the inhibitor concentration at the target membrane plane. Such inhibitors have great potential in terms of substrate selectivity and reduced side effects. Not only for β-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.

Membrane Trafficking Pathways inAlzheimer's Disease

“…BACE1 possesses two active-site motifs (D*TGS and D*SGT) in the extracellular domain, which contribute to the proteolysis of its substrates. It has maximal activity at acidic pH (26) in agreement with BACE1 being localized mainly in endosomes, lysosomes and the TGN, although some BACE1 is transiently associated with the plasma membrane as well. In concordance, agents that increase endosomal pH also inhibit β-secretase activity (18).…”

Alzheimer’s disease: relevant molecular and physiopathological events affecting amyloid-β brain balance and the putative role of PPARs

“…Increasing interest in β- and γ-secretase clustering has emerged in various investigations, which indicate that this event is favored in cholesterol-rich domains of the plasma membrane, termed lipid rafts (Kapoor et al, 2010; Marquer et al, 2011). Some authors have proposed that lipid rafts would be appropriate targets of potential therapeutic interventions against AD (Ben Halima and Rajendran, 2011). …”

Regulation of Cerebral Cholesterol Metabolism in Alzheimer Disease

“…106, 107 A new development linking a BACE-1 inhibitor to a cholesterol molecule enriches the expression of the inhibitor in lipid rafts, increasing its potency. 108, 109 It is hoped that this type of targeted therapy, now in its infancy, may have substantial impact on this debilitating illness.…”