Abstract
Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,” which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be part of a new wave of AD therapeutics.
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Introduction
Alzheimer’s disease (AD) is the most common cause of dementia affecting more than 6 million Americans. In 2021, AD and other dementias cost $355 billion in healthcare, and these costs could exceed $1 trillion by 2050 [1]. Early symptoms include memory loss and behavioral changes; in late stages of AD cognitive decline interferes with most everyday activities. While acetylcholinesterase inhibitors and N-methyl-D-aspartic acid (NMDA) antagonists alleviate cognitive and behavior symptoms [2], there are no treatments which delay or stop disease progression. Earlier this year the FDA approved aducanumab, the first novel therapy for AD in almost two decades. Aducanumab, a human monoclonal antibody which targets aggregated amyloid-beta (Aβ), reduced amyloid plaques in the brain, and is expected to delay cognitive decline [2, 3].
AD pathology is characterized by the deposition of Aβ plaques in brain tissue [4]. While the underlying disease mechanisms are complex and still being elucidated, multiple lines of evidence support the “amyloid hypothesis,” which posits that the accumulation of Aβ peptides initiates a chain of pathological events, including formation of neurofibrillary tangles and inflammatory responses, leading to widespread neurodegeneration and ultimately AD [5, 6]. The gene encoding the amyloid precursor protein (APP) was identified on chromosome 21, which corresponded with Down’s syndrome individuals who consistently exhibited AD [7, 8]. Mutations in APP, Presenilin-1 (PS1), and Presenilin-2 (PS2) have been linked to early-onset familial AD (FAD), which begins before age 60–65 [9,10,11]. APP mutations clustered at or near sites of APP proteolytically processed by secretases to promote amyloidogenic Aβ [12,13,14]. PS1 and PS2 mutations were demonstrated to directly affect APP cleavage by γ-secretase and cause toxic gain of function to increase the ratio of Aβ42/Aβ40 [15, 16]. Finally, advances in brain imaging and cerebrospinal (CSF) biomarker studies on AD patients have shown that the presence of Aβ precedes about two decades or more before other pathological characteristics [35], it was hypothesized that other co-factors could stimulate the inactive pool of γ-secretase. Discoveries of γ-secretase modulatory proteins (GSMPs), non-essential subunits which can bind to and modulate γ-secretase in response to cellular and environmental changes, have added an interesting layer of regulation [33, 34]. Multiple studies have identified GSMPs which regulate γ-secretase activity and substrate specificity and are dependent on specific contexts: GSAP by aging [36, 37], IFITM3 by innate immunity and aging [38], Hif-1α by hypoxia [39], and SERP1 by ER stress [40]. GSMPs therefore have become implicated in the development of therapeutics for AD.
Learning from γ-secretase Inhibitors
Targeting γ-secretase has been challenging due to its wide range of γ-secretase substrates. γ-secretase cleaves type I integral transmembrane proteins after shedding of their ectodomains. While over 149 putative substrates have been reported [41], APP and Notch are the most characterized. Notch signaling is crucial for cell fate decisions during development, the maintenance and differentiation of neuronal stem cells [42, 43]. After cleavage by furin-like protease in the Golgi and ADAM metalloproteases at S1 and S2 respectively, Notch is cleaved by γ-secretase at S3 (analogous to the ε-cleavage site of APP) to release the Notch intracellular domain, which translocates to the nucleus and acts as a transcription factor to activate target genes [44].
γ-Secretase inhibitors (GSIs) failed in clinical trials due to nonselective inhibition of substrates. Semagacestat and Avagacestat are among the most widely known cases (Fig. 3). Semagacestat (LY-450,139) terminated in phase III due to increased risk for skin cancer, associated with inhibition of Notch1 signaling, and cognitive worsening [45,46,47,Chemical biology of γ-secretase For many years, structural and functional insights of γ-secretase came from chemical probes derived from GSIs and GSMs [57, 77]. Photoaffinity labeling (PAL) has been a valuable tool for target identification of small molecules [78]. Photoaffinity probes, or photoprobes, contain a photoreactive group which crosslinks to binding targets upon UV irradiation and a reporter tag which enables purification or monitoring of the target. The alkyne handle has been the primary choice for reporter tag due to the ability to “click” on a biotin or fluorophore group using Cu-catalyzed azide-alkyne cycloaddition [57, 60]. The earliest photoprobes were based on transition state inhibitors directed at the active site of γ-secretase, such as L-685,458 (L458) and III-31-C [79, 80]. L458-based probes, which individually labeled subsites of the active site, identified PS1 as the catalytic subunit of γ-secretase [20]. A III-31-C-based probe was used in competitive labeling studies to characterize GSIs into different mechanistic classes [81]. More recently, the binding site of BMS-708,163 was mapped by photoprobes with cleavable linkers [82]. Peptide map** using LC–MS/MS demonstrated that the BMS-708,163 probe inserted into L282 of PS1, which was confirmed with molecular dynamic simulations. L282 is located on the inhibitory loop near the endoproteolytic site required for ɣ-secretase activation, suggesting that BMS-708,163 acts as a pan inhibitor of ɣ-secretase. The report was consistent with previous studies that had challenged Notch-sparing mechanism of BMS-708,193 [52, 53]. As GSMs were developed, PAL was employed to identify their binding targets. GSM probes were incubated in HeLa membranes, and then UV irradiated to crosslink them to nearby protein targets and followed by click chemistry with biotin-azide. Biotinylated proteins were then captured with streptavidin beads and analyzed by Western blot. GSM-1 and GSM-2-based probes were found to label PS1-NTF in both reconstituted PS1 and native forms of the ɣ-secretase complex in HeLa membranes [83]. Their labeling was blocked by excess of the parent compounds, demonstrating the specificity of the probe for PS1. Furthermore, GSM-1 enhanced the labeling of the L458-based probe GY4-P1, suggesting that carboxylic acid GSMs modulate γ-secretase by allosterically binding to PS1 and altering the conformation of the active site. Imidazole GSM-based probes RO-57-BpB and E2012-BPyne also labeled PS1-NTF in membranes and live cells [84, 85]. Competitive labeling by these probes revealed that GSMs and GSIs bind to multiple, distinct binding sites on PS1-NTF (Fig. 7). Furthermore, labeling of E2012-BPyne, but not acid GSM probes, was significantly enhanced in the presence of L458, which suggests the binding of L458 induces a more favorable conformation for E2012 to PS1. Together, the PAL studies on small molecule GSIs and GSMs have greatly improved our understanding of their mechanisms and laid the foundation for the subsequent molecule-bound crystal structures. Advances in cryo-EM have enabled detailed reports of the γ-secretase complex, with clear assignment of the transmembrane domains and precise location of the active site [86,87,88]. Structures of γ-secretase bound to APP and Notch have revealed key features of substrate recognition. Upon moving into the active site, the α-helix of the substrate transmembrane domain unwinds and extends into a β-strand to prepare for proteolytic cleavage. Many FAD mutations of PS1 line the substrate-binding cavity and while their mechanisms are unclear, they could alter substrate binding or unwinding. Finally, comparison of the two bound structures site showed notable differences in recognition by APP and Notch, which could be used as a framework to design substrate-selective inhibitors. Recently, the structures of γ-secretase bound to Semagacestat, Avagacestat L458, and the GSM E2012 have been reported [89]. The identification of their binding sites has helped elucidate the recognition and molecular mechanisms of these small molecules. Semagacestat, Avagacestat, and L458 occupy the same binding pocket in PS1 (Fig. 8) and overlap with the β-strand of APP and Notch. Their location suggests that the inhibitors block substrate recruitment into catalytic site. Displacing the substrate beta-strand could be a key strategy to designing more substrate selective GSIs. Key differences were also observed in recognition of the structurally distinct inhibitors. Comparing Semagacestat and Avagacestat, the binding of the bulkier Avagacestat induced more conformational changes to PS1 than Semagacestat binding. Additionally, L458 directly coordinated with the catalytic aspartate residues in PS1, confirming its role as a transition state inhibitor. E2012 was previously known to bind to an allosteric site on PS1 and enhanced binding of L458 [85]. Recognition of E2012 demonstrated the methylimidazole and phenyl groups inserted into a hydrophobic pocket between PS1 and NCT. E2012 was stabilized by a hydrogen bond between the methylimidazole and Tyr106 on loop-1 of PS1 (Fig. 9A). Loop-1 is known to interact with substrate proteins and coordinate between the substrate docking site and catalytic site, suggesting how GSMs can influence the active site of γ-secretase. Concurrent mutagenesis studies revealed that loop-1 is essential for γ-secretase’s processive cleavage and a critical binding site by heterocyclic GSMs [90]. A Visualization of γ-secretase bound to E2012. PS1 is represented in orange and NCT is represented in green. Hydrogen bond between methylimidazole on E2012 and Tyr106 on PS1 is indicated by the dotted blue line. B Visualization of allosteric site and active site on γ-secretase. γ-secretase subunits represented are PS1 (green), Nicastrin (blue), PEN-2 (pink), and APH-1 (brown). Protein Data Bank entry 7D8X Superimposing the E2012-bound γ-secretase structure in complex with an APP fragment revealed that the flurophenyl and piperidine groups clashed with APP transmembrane domain. Modifying any of the heterocycles on E2012 could improve binding affinity and/or selectivity for imidazole-like GSMs. GSMs bind to multiple allosteric sites on γ-secretase, which in turn may alter conformation of the active site (Fig. 9B) [85]. While these structural studies will need to be supported by experimental data, they can be applied towards rational design of the next generation GSIs and GSMs for AD therapeutics.Cryo-EM images of γ-secretase: a wellspring for drug design
Conclusion and future perspectives
While targeting γ-secretase has proven challenging, it should not diminish its potential as a crucial target for AD pathogenesis. The serious toxicities that halted clinical studies of GSIs demonstrated there were many knowledge gaps about γ-secretase biology and underestimation of its nuanced proteolysis before the compounds were evaluated in humans [49]. GSMs aim to stimulate γ-secretase’s carboxypeptidase-like trimming of Aβ peptides to their shorter, less pathogenic forms. Over the past two decades, industry and academic groups have optimized the potency and CNS penetration of GSMs, several of which have started clinical trials. The success of small molecule GSMs, as with other Aβ-targeted therapies, also depend on being administered in the early stages of AD pathology well before clinical manifestations. Amyloid-based biomarkers and diagnostics will be vital to identifying and monitoring trial subjects. The development of the first GSM-based radiotracer suggests that that γ-secretase expression could be monitored in AD patients.
In the past several years, detailed structures of γ-secretase have emerged. These structures have already been used in computational docking studies for GSMs [91]. Modeling GSMs with varying chemotypes could be insightful for comparing their mechanisms of recognizing and altering substrate and enzyme transmembrane domains. The latest γ-secretase structures bound to GSIs and E2012 offer a wealth of information for the design and lead optimization of more potent and substrate-selective small molecules. Drug combinations using drugs which act on distinct targets or show different mechanisms of action have been commonly been used in cancer [92]. A few combination therapies could involve (1) distinct structural classes of GSMs (2) GSMs and inhibitors of tau in neurofibrillary tangles, and (3) GSMs and agents which stimulate Aβ clearance.
Our understandings of γ-secretase regulation, structure, and function have built upon each other like a tide. The approval of the first Aβ-targeted therapy will undoubtedly bring in a new wave of AD therapeutics, and GSMs will be at the forefront.
Availability of data and materials
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Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ:
-
Amyloid-beta
- APP:
-
Amyloid precursor protein
- PS1:
-
Presenilin-1
- PS2:
-
Presenilin-2
- FAD:
-
Familial Alzheimer’s disease
- CSF:
-
Cerebrospinal fluid
- NCT:
-
Nicastrin
- Aph-1:
-
Anterior pharynx defective 1
- Pen-2:
-
Presenilin enhancer-2
- NTF:
-
N-terminal fragment
- CTF:
-
C-terminal fragment
- C99:
-
C-terminal fragment of APP
- GSMP:
-
γ-Secretase modulatory protein
- GSI:
-
γ-Secretase inhibitor
- GSM:
-
γ-Secretase modulator
- COX:
-
Cyclooxygenase
- CYP:
-
Cytochrome P
- hERG:
-
Human ether-a-go-go
- CNS MPO:
-
Central nervous system multi parameter optimization
- LLE:
-
Ligand-lipophilicity efficiency
- ALT:
-
Alanine aminotransferase
- PAL:
-
Photoaffinity labeling
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Acknowledgements
We thank J.Y. Hur for critically reading the manuscript and support from Memorial Sloan Kettering Cancer Center.
Funding
This work is supported by NIH grant R01NS096275 (YML), RF1AG057593 (YML), R01AG061350 (YML), the JPB Foundation (YML), the MetLife Foundation (YML), Cure Alzheimer’s Fund (YML), The Edward and Della L. Thome Memorial Foundation (YML) and Coins for the Alzheimer's Research Trust (YML). JEL is supported by F31AG064813. Authors also acknowledge the MSK Cancer Center Support Grant/Core Grant (Grant P30 CA008748), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC, and the William Randolph Hearst Fund in Experimental Therapeutics.
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LYM is a co-inventor of the intellectual property (assay for gamma secretase activity and screening method for gamma secretase inhibitors) owned by MSKCC and licensed to Jiangsu Continental Medical Development.
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Luo, J.E., Li, YM. Turning the tide on Alzheimer’s disease: modulation of γ-secretase. Cell Biosci 12, 2 (2022). https://doi.org/10.1186/s13578-021-00738-7
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DOI: https://doi.org/10.1186/s13578-021-00738-7