ß- and g-secretases generate the amyloid ß-protein (Aß) 1 from amyloid ß-protein precursor (APP) that is the hallmark of Alzheimer disease. Gamma (g)?-secretase has also been implicated in the cleavage of other substrates, the most notable one being the Notch receptor. Inhibition of Notch processing is the key factor of mechanism-based side effects associated with g-secretase inhibitors.

Vassar R in 2000 discussed about a beta generating enzyme in Alzheimer disease (AD) 2. Esler in 2002 carried out activity-dependent isolation of the presenilin- g-secretase complex. The functional g-secretase complex was isolated by using an immobilized active site-directed inhibitor of the protease. Presenilin heterodimers and nicastrin bound specifically to this inhibitor under conditions tightly correlating with protease activity, whereas several other presenilin-interacting proteins (beta-catenin, calsenilin, and presenilin-associated protein) did not bind. Moreover, anti-nicastrin antibodies immunoprecipitated g-secretase activity from detergent-solubilized microsomes. Unexpectedly, C83, the major endogenous amyloid-beta precursor protein substrate of g-secretase, was also quantitatively associated with the complex 3.

Structural Characteristics
AD is characterized by the progressive accumulation of Aß  in brain regions subserving memory and cognition. ß-Secretase is a single membrane-spanning aspartyl pro-tease expressed at high levels in neurons 2?-Secretase is also an aspartyl protease but with an unprecedented intramembranous catalytic site that is required for the cleavage of a wide range of type I membrane proteins that include APP and the Notch receptors3. g-secretase is a multi-subunit protease complex, which is an integral membrane protein that cleaves single-pass transmembrane proteins. g???secretase complex consists of four individual proteins: presenilin, nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). PEN-2 associates with the complex via binding of a transmembrane domain of presenilin. APH-1, which is required for proteolytic activity, binds to the complex via a conserved alpha helix interaction motif and aids in initiating assembly of premature components4,5.  Substrate of g?? secretase is amyloid precursor protein, a large integral membrane protein that, which is cleaved by both g and b secretase, into a short 39-42 amino acid peptide known as amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of AD patients. Substrate recognition occurs via nicastrin ectodomain binding to the N-terminus of the target, which is then passed via a poorly understood process between the two presenilin fragments to a water-containing active site at which the catalytic aspartate residue resides. Structure of novel g-secretase inhibitor is [1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-ylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenyl-pentyl]-carbamic acid tert-butyl ester (CBAP), which not only physically interacts with presenilin 1 (PS1), but upon chronic treatment produces a "pharmacological knock-down" of PS1 fragments 6

Mode of Action
Development of AD pathology appears to be causally related to age-dependent changes in the metabolism of the , leading to its enhanced aggregation and deposition. g-Secretase is a crucial enzyme for the generation of antibody from the APP and thus represents a valid potential therapeutic target for the treatment or prevention of AD. Enzyme activity has been shown to be dependent on the expression of presenilins and the identification of inhibitors containing transition-state analogue mimics, together with mutagenesis and knockout studies, confirms that presenilins may provide at least a component of the catalytic site for this putative aspartyl protease. Considerable effort has been expended to identify compounds which specifically reduce g-secretase activity in the central nervous system, and those with the appropriate properties are being utilized in on-going proof-of-concept studies in animals and humans, to determine the extent and duration of g-secretase inhibition required to elicit therapeutic benefits. g-secretase-mediated substrate cleavage fall into the category of 'regulated intramembrane proteolysis'. g -secretase itself displays characteristics of an aspartyl protease as it is inhibited by structurally diverse transition-state mimetics for this class of protease. These include compounds with moderate affinities such as substrate-based difluoroketones or an inhibitor with potency in the low-nM range that contains a hydroxyethylene dipeptide isostere 7,8.


Cause of Alzheimer's disease,
sequential action of b-secretase and g-secretase enzymes leads to releases the APP. This peptide entity is thought to be the cause of AD. Therefore, inhibiting either of the two critical enzymes involved in antibody peptide generation provides opportunities to develop drugs which could have the potential to slow down the progression and delay the onset of AD 9.

Gamma-secretase inhibitors may have the ability to interfere with both intermolecular and intramolecular cleavage reactions, which require presenilins. Thus, from a drug-discovery point of view it is important that g-secretase inhibitors interfere with presenilin functions 10.

Tunicamycin-induced expression of the chaperone BiP, an indicator of the unfolded protein response, was not changed in the presence of functional g-secretase inhibitors. These findings suggest that presenilins are multi-functional proteins and that gamma-secretase inhibitors are valuable tools to discriminate presenilin-associated protease functions from unrelated functions.


  1. Selkoe DJ (2001). Alzheimer's disease: genes, proteins, and therapy. Physiol Rev., 81:741–766.Vassar R, Citron M. (2000). A beta-generating enzymes: recent advances in beta- and gamma-secretase research. Neuron, 27:419–422.
  2. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, Wolfe MS (2002).  Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate. PNAS., 99:2720–2725.
  3. Kaether C, Haass C, Steiner H. (2006). Assembly, trafficking and function of gamma-secretase. Neurodegener Dis., 3(4-5):275-283.
  4. Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, Pedersen K, Han W, Thomas P, Lundkvist J, Hao YH, Yu G (2004). A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex. J Biol Chem., 279(6):4144-4152.
  5. Beher D, Wrigley JD, Nadin A, Evin G, Masters CL, Harrison T, Castro JL, Shearman MS (2001). Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology. J. Biol. Chem., 276:45394–45402.
  6. Shearman MS, Beher D, Clarke EE, Lewis HD, Harrison T, Hunt P, Nadin A, Smith AL, Stevenson G, Castro JL (2000.) L-685,458, an aspartyl protease transition state mimic, is a potent inhibitor of amyloid beta-protein precursor gamma-secretase activity. Biochemistry, 38:8698–8704.
  7. Brown MS, Ye J, Rawson RB, Goldstein JL (2000). Regulated intramembrane proteolysis: a control mechanism   conserved from bacteria to humans. Cell, 100:391–398.
  8. Hardy J, Selkoe DJ (2002). The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science, 297(5580):353-356.
  9.   Mumm JS, Kopan R (2000) Notch signaling: from the outside in. Dev. Biol., 228:151-165.


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