Presenilin (PS)-1 or -2 act as the catalytic component/essential co-factor of the γ-secretase complex responsible for the final carboxy-terminal cleavage of amyloid precursor protein (APP) [6] in the generation of amyloid beta (Aβ) [1,11]. Given that the accumulation and aggregation of Aβ in the brain is pivotal in the development of Alzheimer's disease (AD), inhibition of PS activity is one mechanism being investigated as a therapeutic option for AD [5]. Several small molecule inhibitors of PS-1 have been investigated, with some reaching early clinical trials, but none have been formally approved. Dewji et al. (2015) have reported that small peptide fragments of human PS-1 can significantly inhibit Aβ production (total Aβ, Aβ40 and Aβ42) both in vitro and when infused in to the brains of APP transgenic mice [4]. The most active small peptides in this report were P4 [PMID: 25923432] and P8 [PMID: 25923432], from the amino-terminal domain of PS-1.

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4. Dewji NN, Singer SJ, Masliah E, Rockenstein E, Kim M, Harber M, Horwood T. (2015) Peptides of Presenilin-1 Bind the Amyloid Precursor Protein Ectodomain and Offer a Novel and Specific Therapeutic Approach to Reduce ß-Amyloid in Alzheimer's Disease. PLoS ONE, 10 (4): e0122451. [PMID:25923432]

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8. Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H et al.. (2009) Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res, 69 (19): 7672-80. [PMID:19773430]

9. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, Harrison B et al.. (2009) Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther, 331 (2): 598-608. [PMID:19671883]

10. Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW, Hom RK, Konradi AW, Marugg JL, Mattson MN, Neitzel ML et al.. (2013) Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch. J Med Chem, 56 (13): 5261-74. [PMID:23713656]

11. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T. (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature, 422 (6930): 438-41. [PMID:12660785]

12. Xin Z, Peng H, Zhang A, Talreja T, Kumaravel G, Xu L, Rohde E, Jung MY, Shackett MN, Kocisko D et al.. (2011) Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach. Bioorg Med Chem Lett, 21 (24): 7277-80. [PMID:22061640]