%0 Journal Article
%T Modulation of ¦Ã-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice
%A Rogers Kathryn
%A Felsenstein Kevin M
%A Hrdlicka Lori
%A Tu Zhiming
%J Molecular Neurodegeneration
%D 2012
%I BioMed Central
%R 10.1186/1750-1326-7-61
%X Background A hallmark of Alzheimer¡¯s disease is the presence of senile plaques in human brain primarily containing the amyloid peptides A¦Â42 and A¦Â40. Many drug discovery efforts have focused on decreasing the production of A¦Â42 through ¦Ã-secretase inhibition. However, identification of ¦Ã-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of ¦Ã-secretase to shift A¦Â production to favor shorter, less amyloidogenic peptides than A¦Â42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called ¦Ã-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer¡¯s disease. Results Here we describe EVP-0015962, a novel small molecule ¦Ã-secretase modulator. EVP-0015962 decreased A¦Â42 in H4 cells (IC50 = 67 nM) and increased the shorter A¦Â38 by 1.7 fold at the IC50 for lowering of A¦Â42. A¦ÂTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other ¦Ã-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a ¦Ã-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased A¦Â42 and did not alter A¦ÂTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt A¦Â deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced A¦Â aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. Conclusions EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective ¦Ã-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of A¦Â42, attenuated memory deficits, and reduced A¦Â plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that ¦Ã-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer¡¯s disease.
%K ¦Ã-secretase
%K Modulation
%K NSAID
%K Cognition
%K Amyloid
%K Alzheimer¡¯s disease
%U http://www.molecularneurodegeneration.com/content/7/1/61