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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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)  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 . 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 . The most active small peptides in this report were P4 [PMID: 25923432] and P8 [PMID: 25923432], from the amino-terminal domain of PS-1.
1. Ahn K, Shelton CC, Tian Y, Zhang X, Gilchrist ML, Sisodia SS, Li YM. (2010) Activation and intrinsic gamma-secretase activity of presenilin 1. Proc. Natl. Acad. Sci. U.S.A., 107 (50): 21435-40. [PMID:21115843]
2. Alzheimer Research Forum. DRUGS IN CLINICAL TRIALS: BMS-708163. Accessed on 06/09/2013. Modified on 06/09/2013. Alzheimer Research Forum, http://www.alzforum.org/drg/drc/detail.asp?id=124
3. Borgegard T, Juréus A, Olsson F, Rosqvist S, Sabirsh A, Rotticci D, Paulsen K, Klintenberg R, Yan H, Waldman M et al.. (2012) First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms. J. Biol. Chem., 287 (15): 11810-9. [PMID:22334705]
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]
5. Golde TE, Younkin SG. (2001) Presenilins as therapeutic targets for the treatment of Alzheimer's disease. Trends Mol Med, 7 (6): 264-9. [PMID:11378516]
6. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325 (6106): 733-6. [PMID:2881207]
7. Kreft AF, Martone R, Porte A. (2009) Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease. J. Med. Chem., 52 (20): 6169-88. [PMID:19694467]
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]
Database page citation:
A22: Presenilin. Accessed on 29/03/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=727.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol. 172: 6024-6109.