Therapies opposing cleavage of amyloid precursor protein (APP) into A? peptides and resultant cerebral amyloidosis, a key pathological feature of AD, have become a primary focus in recent years. The main targets have been ?- and ?-secretase, the two proteases that cleave APP at the amino and carboxyl-terminus of the A? peptide, respectively and, hence, are responsible for A? peptide generation. An alternative strategy, the activation of ?-secretase, has scarcely been investigated. ?-secretase cleaves APP within the A? peptide domain and precludes its generation, thereby promoting the non-amyloidogenic pathway of APP proteolysis. ?-secretase activation also generates the putatively neuroprotective sAPP-?. In addition, previous studies have shown that enhanced activation of ADAM10, a primary candidate ?-secretase, has reduced A? generation and prevented cognitive impairment in a mouse model of AD. Our previous findings suggest that EGCG promotes non-amyloidogenic APP proteolysis by in vitro activation of ADAM10 and, similarly, prevent ?-amyloid pathology in vivo. Recently, we found that EGCG functions through an estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. Further these events are positively correlated with presence of the gallate group of these phenolic compounds. Furthermore, we have shown that octyl gallate (OG) has a significantly profound effect on promoting ?-secretase cleavage of APP thus limiting A? production in neuron-like N2a cells expressing human wild-type APP compared to EGCG. Most recently, we found that exogenous human recombinant sAPP-? protein promotes non-amyloidogenic APP proteolytic processing through specifically interacting with BACE1, a primary ?-secretase candidate, in cultured cells. This interaction of sAPP-? with BACE1 inhibited its subsequent cleavage of full-length APP and resultant further decreased A? generation. The goal of the proposed research is to define this non-amyloidogenic mechanism in OG and identify potential molecular drug targets, which are essential for formulating novel, effective treatments against AD. In this proposal we hypothesize that ADAM10 activating compound, octyl gallate (OG) produced from the gallic acid of various plant tannins, will increase non-amyloidogenic/alpha-secretase proteolysis of APP, and reduce cerebral amyloidosis in a transgenic mouse model of AD. We expect to clearly define this non-amyloidogenic APP processing mechanism promoted by OG, and, consequently, identify potential molecular drug targets, which are essential for formulating novel, effective treatments against AD. This work will be completed by investigation of the following aims: (I) Investigate the role of estrogen receptor (ER) signaling in OG-promoted anti-amyloidogenic APP ?-secretase proteolysis;Characterize sAPP-? mediation of OG-induced anti-amyloidogenic APP processing;(III) In vivo evaluation of the effect of octyl gallate (OG) for the promotion of anti-amyloidogenic APP ?-secretase proteolysis. At the end of these experiments, these studies will provide the molecular basis for the future development of OG as novel and pharmacologically safe agents for Alzheimer's disease prevention/treatment.
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