Secretase Modulators in the Treatment of Alzheimer Disease
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CLINICAL IMPLICATIONS OF BASIC NEUROSCIENCE RESEARCH SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD, PhD Potential Use of ␥-Secretase Modulators in the Treatment of Alzheimer Disease Steven L. Wagner, PhD; Rudolph E. Tanzi, PhD; William C. Mobley, MD, PhD; Douglas Galasko, MD lthough significant progress has occurred in the past 20 years regarding our under- standing of Alzheimer disease pathogenesis, we have yet to identify disease- modifying therapeutics capable of substantially altering the clinical course of this preva- lent neurodegenerative disease. In this short review, we discuss 2 approaches that are Acurrently being tested clinically (␥-secretase inhibition and ␥-secretase modulation) and empha- size the significant differences between these 2 therapeutic approaches. We also discuss certain genetic- and biomarker-based translational and clinical trial paradigms that may assist in devel- oping a useful therapeutic agent. Arch Neurol. 2012;69(10):1255-1258. Published online July 16, 2012. doi:10.1001/archneurol.2012.540 Genetic models have long been used to de- tin), and according to the American Heart vise and evaluate rational approaches to the Association (http://www.heart.org), stat- treatment of high-prevalence diseases such ins can safely elicit a selective lowering of as coronary artery disease and stroke. One low-density lipoprotein cholesterol levels of the most notable examples was in the and long-term administration of statins can pioneering studies of Mabuchi et al1 re- reduce the incidence of coronary artery dis- porting the highly beneficial effects of a ease and stroke by more than 25% to 30%. 3-hydroxy-3-methylglutaryl–coenzyme A Alzheimer disease (AD) affects approxi- reductase inhibitor, compactin, in pa- mately 1 in 8 Americans aged 65 years or tients with familial hypercholesterolemia. older. Unfortunately, unlike coronary ar- 3-Hydroxy-3-methylglutaryl–coenzyme A tery disease and stroke, there are currently reductase is the enzyme that catalyzes the no effective disease-modifying or preven- conversion of 3-hydroxy-3-methylglutaryl– tive therapies available. However, more than coenzyme A to mevalonate, the rate- 200 different mutations have been identi- limiting step in cholesterol synthesis. This fied in 3 genes associated with an autoso- historic study involving 7 patients with a mal dominant form of AD, referred to as mutation in the low-density lipoprotein re- early-onset familial Alzheimer disease ceptor gene (LDLR) reported the success- (EOFAD). It is an aggressive form of AD that ful lowering of low-density lipoprotein cho- has served as a template for many of the cel- lesterol levels without changing or even lular and transgenic animal models being slightly increasing high-density lipopro- used to study the pathogenesis of AD and tein cholesterol levels. That small proof- is relevant to the more common late-onset of-concept clinical pharmacodynamic study 2 eventually paved the way to the subse- AD. The 3 genes causally implicated in quent development of a related class of mol- EOFAD, which typically affects carriers be- ecules known as the synthetic statins (eg, fore age 65 years and sometimes as early as fluvastatin, atorvastatin, and rosuvasta- the third or fourth decades, are APP (amy- loid precursor protein), PSEN1 (presenilin Author Affiliations: Department of Neurosciences, University of California, San 1), and PSEN2 (presenilin 2). The preseni- Diego, School of Medicine, La Jolla (Drs Wagner, Mobley, and Galasko); and lin genes encode 2 highly homologous pro- Genetics and Aging Research Unit, Department of Neurology, Massachusetts teins that can independently assemble along General Hospital, Charlestown (Dr Tanzi). with 3 other membrane-associated pro- ARCH NEUROL / VOL 69 (NO. 10), OCT 2012 WWW.ARCHNEUROL.COM 1255 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 substrate of ␥-secretase, and the Membrane Notch-1 receptor intracellular do- main peptide plays an important role in the differentiation of multiple cell types.4 The GSIs also cause accumu- lation of the ␥-secretase substrate C99 (the C-terminal fragment of APP gen- Pen-2 erated by the A-cleaving enzyme γ Aβ BACE 1) as well as C-terminal frag- 40 PS-NTF 38 42 ments from a number of other type 1 37 39 1 membrane proteins believed to be Aβ 5 AICD degraded by ␥-secretase. Eli Lilly and 48 49 Co recently reported (http://www.lilly PS-CTF ε .com) that in 2 phase 3 clinical trials involving more than 2600 mildly to Nicastrin moderately affected patients with Aph-1 probable AD, the GSI semagacestat failed to slow disease progression and led to worsened cognition and per- formance of activities of daily living. In addition, semagacestat was asso- ciated with an increased risk of skin cancer. The explanation for these dis- appointing clinical outcomes is cur- rently unknown but may be mecha- Figure 1. ␥-Secretase processing of amyloid precursor protein C-terminal fragments (CTFs). A cartoon illustration shows the various subunits of the ␥-secretase enzyme complex performing a number of different nistically related to inhibiting the putative ␥-secretase–mediated proteolytic activities. Assembly and maturation of the ␥-secretase enzyme ␥-secretase enzyme complex and at- begins with the formation of a binary complex between nicastrin and anterior pharynx defective 1 (Aph-1). tenuating the processing of 1 or more Presenilin (PS) binds to the nicastrin/Aph-1 complex to form an inactive trimeric complex. The PS N-terminal fragment (NTF) and the PS-CTF collectively harbor the catalytic center of ␥-secretase, which of its substrates including the C- requires binding of presenilin enhancer 2 (Pen-2) for the endoproteolysis of PS into the PS-NTF and the terminal fragments of APP, Notch-1, PS-CTF, rendering activation of ␥-secretase. The active ␥-secretase enzyme can cleave the amyloid and possibly other substrates.5 precursor protein CTF at numerous sites, yielding a host of peptide products (amyloid precursor protein intracellular domain [AICD], -amyloid (A) 1-42, A1-40, A1-39, A1-38, and A1-37). The relative size Interestingly, the vast majority of of the curved arrows at the ␥ sites indicates the relative use of each processing site. The ε cleavages (larger EOFAD-linked mutations do not cor- curved arrows at amino acids 48 and 49 of the 99–amino acid–long amyloid precursor protein CTF) relate with an overall increase in generate the AICDs, which remain inside the cell (as indicated by the direction of the right arrow) and may ␥-secretase activity, nor do they ap- actually travel to the nucleus, while the various A peptides are released extracellularly (as indicated by the  direction of the left arrow) immediately on cleavage by ␥-secretase within the membrane. The different pear to increase total A peptide lev- colors correspond to the different proteolytic processing products. els. Instead, most appear to cause a 2-fold increase in the ratio of A42/ teins, namely, nicastrin, anterior phar- EOFAD, these and perhaps others A40 (Figure 2). This increased ynx defective 1, and presenilin that develop further downstream (eg, A42/A40 ratio is a highly repro- enhancer 2 (Pen-2), into a large mem- neurofibrillary tangles, another ma- ducible biochemical phenotype (in brane-bound enzymatic complex jor neuropathological hallmark of vitro and in vivo) for the predomi- (Figure 1) that plays a key role in AD) arise owing to a change in the ra- nant effect of the more than 200 metabolizing a large number of type tio of cerebral levels of A42 relative EOFAD-linked genetic mutations, in- 1 membrane proteins, including APP.2 to the next longest A peptide, A40 cluding a number of mutations in APP The rationale for targeting this enzy- (which is by far the most abundant (those proximal to the ␥-secretase matic complex, referred to as ␥-secre- of all secreted A peptides), increas- cleavage site in the APP protein), all tase, as a therapeutic approach for AD ing the A42/A40 ratio approxi- of those in PSEN2, and most of the stems from the fact that ␥-secretase mately 2-fold.2 Initial therapeutic in- large number of mutations in PSEN1.2 performs the terminal series of pro- terventions targeting ␥-secretase Therefore, a therapeutic rationale teolytic cleavages that generate and re- focused on curbing total A peptide based on this EOFAD genetics model lease extracellularly a number of pep- production by directly inhibiting would entail modulating ␥-secretase tides known collectively as -amyloid ␥-secretase activity through a class of activity (decreasing the A42/A40 (A).2 Most secreted A peptides compounds referred to as ␥-secre- ratio), not inhibiting this important range in size from approximately 34 tase inhibitors (GSIs).3 The GSIs at- enzyme complex. The feasibility of to 42 amino acids (Figure 1). One of tenuate the production of all major A this more selective EOFAD genetics- these, A42 (42 amino acids long), peptide variants (eg, A42, A40, based approach was first identified is the major peptide found in neu- A39, A38, and A37) equiva- using a series of nonsteroidal anti- ritic plaques and diffuse amyloid de- lently (Figure 2) and inhibit the gen- inflammatory drug (NSAID)–like posits, neuropathological lesions eration of an APP intracellular do- compounds, eg, ibuprofen and sulin- found in abundance in the brains of main and the Notch-1 receptor dac sulfide.6 However, the NSAID-like patients with AD at autopsy. In intracellular domain. Notch is a key compounds lack potency (Ն50- ARCH NEUROL / VOL 69 (NO. 10), OCT 2012 WWW.ARCHNEUROL.COM 1256 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 100µM in vitro half-maximal inhibi- tory concentrations for selective low- A ering of the A42 level in cell-based assays) and later proved to have very 99 6,7 poor brain penetrance.