%0 Journal Article
%T In Vivo Characterization of a Novel -Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects
%A Lynn A. Hyde
%A Qi Zhang
%A Robert A. Del Vecchio
%A Prescott T. Leach
%A Mary E. Cohen-Williams
%A Lei Chen
%A Gwendolyn T. Wong
%A Nansie A. McHugh
%A Joseph Chen
%A Guy A. Higgins
%A Theodros Asberom
%A Wei Li
%A Dmitri Pissarnitski
%A Diane Levitan
%A Amin A. Nomeir
%A John W. Clader
%A Lili Zhang
%A Eric M. Parker
%J International Journal of Alzheimer's Disease
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/823528
%X Substantial evidence implicates -amyloid (A ) peptides in the etiology of Alzheimer¡¯s disease (AD). A is produced by the proteolytic cleavage of the amyloid precursor protein by - and -secretase suggesting that -secretase inhibition may provide therapeutic benefit for AD. Although many -secretase inhibitors have been shown to be potent at lowering A , some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another -secretase substrate. Here we describe the in vivo characterization of the novel -secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A , Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A . However, additional studies revealed that both partial but sustained lowering of A and complete but less sustained lowering of A were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of A lowering by -secretase inhibitors, it is possible to obtain robust and sustained lowering of A without evidence of Notch-related side effects. 1. Introduction Alzheimer¡¯s disease (AD) is a progressive age-related neurodegenerative disease characterized clinically by memory loss and cognitive dysfunction followed by a disruption of normal daily functions, organ system failure, and, ultimately, death. However, a diagnosis of AD can only be confirmed postmortem by the presence of distinct neuroanatomical hallmarks including senile plaques consisting primarily of ¦Â-amyloid (A¦Â) peptides, neurofibrillary tangles consisting of hyperphosphorylated tau, and substantial neuronal loss, particularly in the hippocampus, an area of the brain which plays a key role in memory. Substantial genetic and neuroanatomical evidence implicates A¦Â peptides in the etiology of Alzheimer¡¯s disease (e.g., [1¨C3]). Therefore, it is thought that a reduction in A¦Â production or an increase in A¦Â clearance will have a beneficial, and potentially disease modifying, effect on the disease. A¦Â is produced by sequential cleavage of amyloid precursor protein (APP) by ¦Â-site APP cleaving enzyme 1 (BACE1) followed by ¦Ã-secretase. Thus, inhibiting ¦Ã-secretase should decrease A¦Â production. Indeed, acute and chronic administration of small molecule ¦Ã-secretase inhibitors
%U http://www.hindawi.com/journals/ijad/2013/823528/