Abstract
δ-secretase, also known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves both amyloid precursor protein (APP) and tau, mediating the amyloid-β and tau pathology in Alzheimer’s disease (AD). Here we report the therapeutic effect of an orally bioactive and brain permeable δ-secretase inhibitor in mouse models of AD. We performed a high-throughput screen and identified a non-toxic and selective δ-secretase inhibitor, termed compound 11, that specifically blocks δ-secretase but not other related cysteine proteases. Co-crystal structure analysis revealed a dual active site-directed and allosteric inhibition mode of this compound class. Chronic treatment of tau P301S and 5XFAD transgenic mice with this inhibitor reduces tau and APP cleavage, ameliorates synapse loss and augments long-term potentiation, resulting in protection of memory. Therefore, these findings demonstrate that this δ-secretase inhibitor may be an effective clinical therapeutic agent towards AD.
Highlights
To date, various inhibitors of d-secretase have been described
D-Becretase, known as asparagine endopeptidase (AEP) or legumain, is a lysosomal cysteine protease that cleaves peptide bonds C-terminally to asparagine residues. d-secretase is involved in various cellular events, including antigen processing, the cleavage of other lysosomal enzymes, osteoclast formation and normal kidney function[1,2,3,4,5]
After cleavage by d-secretase, SET fragments inhibit the activity of protein phosphatase 2A (PP2A), which is responsible for 70% of tau phosphatase activity[12]
Summary
Various inhibitors of d-secretase have been described. Cysteine proteases are physiologically regulated by interacting proteins, such as cystatins, which form a reversible high-affinity complex with the enzyme[10]. Synthetic inhibitors that have been generated to target d-secretase, are generally peptide-based inhibitors, which incorporate an asparagine residue for specificity and halomethylketones, Michael acceptors or acyloxymethylketones, to inhibit the catalytic activity of the enzyme[15,16,17]. Such reactive groups are commonly employed for the inhibition of caspases and cysteine proteases and do not offer much selectivity. An effective small molecule inhibitor of d-secretase has yet to be identified. Using high-throughput screen, we identified compound 11 as a potent and specific small molecular inhibitor of d-secretase. Chronic treatment with compound 11 attenuated tau and APP cleavage in tau P301S and 5XFAD transgenic mouse models, respectively, and ameliorated synaptic dysfunction and cognitive impairments
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