Abstract
Familial Alzheimer’s disease (FAD) is a rare early-onset genetic form of common dementia of old age. Striking in middle age, FAD is caused by missense mutations in three genes: APP (encoding the amyloid precursor protein) and PSEN1 and PSEN2 (encoding presenilin-1 and presenilin-2). APP is proteolytically processed successively by β-secretase and γ-secretase to produce the amyloid β-peptide (Aβ). Presenilin is the catalytic component of γ-secretase, a membrane-embedded aspartyl protease complex that cleaves APP within its single transmembrane domain to produce Aβ of varying lengths. Thus, all FAD mutations are found in the substrate and the enzyme that produce Aβ. The 42-residue variant Aβ42 has been the primary focus of Alzheimer drug discovery for over two decades, as this particular peptide is highly prone to aggregation, is the major protein deposited in the characteristic cerebral plaques of Alzheimer’s disease and is proportionately elevated in FAD. Despite extensive efforts, all agents targeting Aβ and Aβ42 have failed in the clinic, including γ-secretase inhibitors, leading to questioning of the amyloid hypothesis of Alzheimer pathogenesis. However, processing of the APP transmembrane domain by γ-secretase is complex, involving initial endoproteolysis followed by successive carboxypeptidase trimming steps to secreted Aβ peptides such as Aβ42. Recent findings reveal that FAD mutations in PSEN1 and in APP result in the deficient trimming of initially formed long Aβ peptides. A logical drug discovery strategy for FAD could therefore involve the search for compounds that rescue this deficient carboxypeptidase activity. The rare early-onset FAD arguably presents a simpler path to developing effective therapeutics compared to the much more complex heterogeneous sporadic Alzheimer’s disease.
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Abbreviations
- Alzheimer’s disease:
-
(AD)
- amyloid β-peptide:
-
(Aβ)
- amyloid precursor protein:
-
(APP)
- amyloid precursor protein intracellular domain:
-
(AICD)
- 99-residue APP membrane-bound stub:
-
(C99)
- C-terminal fragment:
-
(CTF)
- cryo-electron microscopy:
-
(cryo-EM)
- familial Alzheimer’s disease:
-
(FAD)
- γ-secretase inhibitor:
-
(GSI)
- γ-secretase modulator:
-
(GSM)
- N-terminal fragment:
-
(NTF)
- (polyacrylamide gel electrophoresis):
-
PAGE
- presenilin-1:
-
(PSEN1)
- presenilin-2:
-
(PSEN2)
- transition-state analog inhibitor:
-
(TSA)
- transmembrane domain:
-
(TMD).
References
Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362:329–44.
Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell. 2005;120:545–55.
Cole SL, Vassar R. The role of APP processing by BACE1, the β-secretase, in Alzheimer’s disease pathophysiology. J Biol Chem. 2008;283:29621–5.
Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, et al. Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature. 1991;353:844–6.
Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 1991;349:704–6.
Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256:184–5.
Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322–5.
Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature. 1995;376:775–8.
Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature. 1995;375:754–60.
Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:973–7.
Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2:864–70.
Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med. 1997;3:67–72.
Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, et al. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron. 1996;17:181–90.
Thinakaran G, Harris CL, Ratovitski T, Davenport F, Slunt HH, Price DL, et al. Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors. J Biol Chem. 1997;272:28415–22.
Ratovitski T, Slunt HH, Thinakaran G, Price DL, Sisodia SS, Borchelt DR. Endoproteolytic processing and stabilization of wild-type and mutant presenilin. J Biol Chem. 1997;272:24536–41.
Capell A, Grunberg J, Pesold B, Diehlmann A, Citron M, Nixon R, et al. The proteolytic fragments of the Alzheimer’s disease-associated presenilin-1 form heterodimers and occur as a 100–150-kDa molecular mass complex. J Biol Chem. 1998;273:3205–11.
Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, et al. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis. 1997;3:325–37.
Yu G, Chen F, Levesque G, Nishimura M, Zhang DM, Levesque L, et al. The presenilin 1 protein is a component of a high molecular weight intracellular complex that contains β-catenin. J Biol Chem. 1998;273:16470–5.
De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature. 1998;391:387–90.
Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, et al. Presenilins are required for γ-secretase cleavage of beta-APP and transmembrane cleavage of Notch-1. Nat Cell Biol. 2000;2:463–5.
Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Total inactivation of γ-secretase activity in presenilin-deficient embryonic stem cells. Nat Cell Biol. 2000;2:461–2.
Wolfe MS, Citron M, Diehl TS, Xia W, Donkor IO, Selkoe DJ. A substrate-based difluoro ketone selectively inhibits Alzheimer’s γ-secretase activity. J Med Chem. 1998;41:6–9.
Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Donkor IO, et al. Peptidomimetic probes and molecular modeling suggest Alzheimer’s γ-secretases are intramembrane-cleaving aspartyl proteases. Biochemistry. 1999;38:4720–7.
Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature. 1999;398:513–7.
Wolfe MS, De Los Angeles J, Miller DD, Xia W, Selkoe DJ. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer’s disease. Biochemistry. 1999;38:11223–30.
Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai J-Y, et al. Transition-state analogue inhibitors of γ-secretase bind directly to presenilin-1. Nat Cell Biol. 2000;2:428–34.
Li YM, Xu M, Lai MT, Huang Q, Castro JL, DiMuzio-Mower J, et al. Photoactivated γ-secretase inhibitors directed to the active site covalently label presenilin 1. Nature. 2000;405:689–94.
De Strooper B. Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex. Neuron. 2003;38:9–12.
Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, et al. Activity-dependent isolation of the presenilin/γ-secretase complex reveals nicastrin and a γ substrate. Proc Natl Acad Sci USA. 2002;99:2720–5.
Das C, Berezovska O, Diehl TS, Genet C, Buldyrev I, Tsai JY, et al. Designed helical peptides inhibit an intramembrane protease. J Am Chem Soc. 2003;125:11794–5.
Bihel F, Das C, Bowman MJ, Wolfe MS. Discovery of a subnanomolar helical D-tridecapeptide inhibitor of γ-secretase. J Med Chem. 2004;47:3931–3.
Kornilova AY, Bihel F, Das C, Wolfe MS. The initial substrate-binding site of γ-secretase is located on presenilin near the active site. Proc Natl Acad Sci USA. 2005;102:3230–5.
Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L. et al. An atomic structure of human γ-secretase. Nature. 2015;525:212–7.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019;363:eaaw0930.
Bhattarai S, Devkota S, Meneely KM, Xing M, Douglas JT, Wolfe MS. Design of substrate transmembrane mimetics as structural probes for γ-secretase. J Am Chem Soc. 2020;142:3351–5.
Lanz TA, Himes CS, Pallante G, Adams L, Yamazaki S, Amore B. et al. The γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester reduces Aβ levels in vivo in plasma and cerebrospinal fluid in young (plaque-free) and aged (plaque-bearing) Tg2576 mice. J Pharmacol Exp Ther. 2003;305:864–71.
Barten DM, Guss VL, Corsa JA, Loo AT, Hansel SB, Zheng M, et al. Dynamics of β-amyloid reductions in brain, cerebrospinal fluid and plasma of β-amyloid precursor protein transgenic mice treated with a γ-secretase inhibitor. J Pharm Exp Ther. 2004;312:635043.
Lanz TA, Hosley JD, Adams WJ, Merchant KM. Studies of Aβ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575). J Pharmacol Exp Ther. 2004;309:49–55.
Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, et al. Secretase inhibitors repress thymocyte development. Proc Natl Acad Sci USA. 2001;98:7487–91.
Güner G, Lichtenthaler SF. The substrate repertoire of γ-secretase/presenilin. Sem Cell Dev Biol. 2020;105:27–42.
Kopan R, Ilagan MX. γ-secretase: proteasome of the membrane? Nat Rev Mol Cell Biol. 2004;5:499–504.
Selkoe D, Kopan R. Notch and presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci. 2003;26:565–97.
Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, et al. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997;387:288–92.
Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997;89:629–39.
Wong GT, Manfra D, Poulet FM, Zhang Q, Josien H, Bara T, et al. Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004;279:12876–82.
Searfoss GH, Jordan WH, Calligaro DO, Galbreath EJ, Schirtzinger LM, Berridge BR, et al. Adipsin: a biomarker of gastrointestinal toxicity mediated by a functional γ-secretase inhibitor. J Biol Chem. 2003;278:46107–16.
Crump CJ, Castro SV, Wang F, Pozdnyakov N, Ballard TE, Sisodia SS, et al. BMS-708,163 targets presenilin and lacks notch-sparing activity. Biochemistry. 2012;51:7209–11.
Coric V, Salloway S, van Dyck CH, Dubois B, Andreasen N, Brody M, et al. Targeting prodromal Alzheimer disease with avagacestat: a randomized clinical trial. JAMA Neurol. 2015;72:1324–33.
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50.
Castro MA, Hadziselimovic A, Sanders CR. The vexing complexity of the amyloidogenic pathway. Protein Sci. 2019;28:1177–93.
Mitani Y, Yarimizu J, Saita K, Uchino H, Akashiba H, Shitaka Y, et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci. 2012;32:2037–50.
McCaw TR, Inga E, Chen H, Jaskula-Sztul R, Dudeja V, Bibb JA, et al. Secretase inhibitors in cancer: a current perspective on clinical performance. Oncologist. 2020;7:13627.
Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci USA. 2017;114:E476–E85.
Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, et al. Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009;29:13042–52.
Quintero-Monzon O, Martin MM, Fernandez MA, Cappello CA, Krzysiak AJ, Osenkowski P, et al. dissociation between the processivity and total activity of γ-secretase: implications for the mechanism of Alzheimer’s disease-causing presenilin mutations. Biochemistry. 2011;50:9023–35.
Fernandez MA, Klutkowski JA, Freret T, Wolfe MS. Alzheimer presenilin-1 mutations dramatically reduce trimming of long amyloid β-peptides (Abeta) by γ-secretase to increase 42-to-40-residue Aβ. J Biol Chem. 2014;289:31043–52.
Devkota S, Williams TD, Wolfe MS. Familial Alzheimer’s disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of >45 residues. J Biol Chem. 2021;296:100281.
Wolfe MS. In search of pathogenic amyloid β-peptide in familial Alzheimer’s disease. Prog Mol Biol Transl Sci. 2019;168:71–8.
Bursavich MG, Harrison BA, Blain JF. γ-secretase modulators: new Alzheimer’s drugs on the horizon? J Med Chem. 2016;59:7389–409.
Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature. 2001;414:212–6.
Rynearson KD, Ponnusamy M, Prikhodko O, Xie Y, Zhang C, Nguyen P, et al. Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J Exp Med. 2021;218:e20202560.
Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367:795–804.
Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12:207–16.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–13.
Spanò V, Venturini A, Genovese M, Barreca M, Raimondi MV, Montalbano A, et al. Current development of CFTR potentiators in the last decade. Eur J Med Chem. 2020;204:112631.
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This work was supported by grant AG66986 from the U.S. National Institutes of Health.
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Wolfe, M.S. Targeting γ-secretase for familial Alzheimer’s disease. Med Chem Res 30, 1321–1327 (2021). https://doi.org/10.1007/s00044-021-02744-3
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DOI: https://doi.org/10.1007/s00044-021-02744-3