Selective Secretase Targeting for Alzheimer’s Disease Therapy

Miranda, Alvaro; Montiel, Enrique; Ulrich, Henning; Paz, Cristian

doi:10.3233/jad-201027

Cited by 66Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

Selective Secretase Targeting for Alzheimer’s Disease Therapy

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Miranda, Alvaro, Montiel, Enrique, Ulrich, Henning, Paz, Cristian·2021·Journal of Alzheimer s Disease

DOI 10.3233/jad-201027

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Abstract

Alzheimer's disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979 Verubecestat, LY2886721, Lanabecestat, LY2811376 and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse disease progress. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase activity enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

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γ-secretase inhibitors such as tarenflurbil, avagacestat, and semagacestat lower amyloid beta synthesis by preventing gamma secretase enzyme from functioning.
“This includes γ-secretase inhibitors, such as tarenflurbil (7, Figure 5) [155,156], avagacestat (labeled as 6, Figure 5) [157,158], and semagacestat (5, Figure 5) [159,160]. Their purpose is to lower the synthesis of amyloid beta by preventing the gamma secretase enzyme from functioning.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [156]
γ-secretase inhibitors failed clinical trials because of many side effects.
“γ-secretase inhibitors failed clinical trials because of many side effects (Miranda et al., 2021)”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Miranda et al., 2021
The BACE-1 inhibitor Lanabecestat failed clinical trials due to lack of effectiveness.
“these trials proved unsuccessful due to the lack of effectiveness, as for the BACE-1 inhibitor Lanabecestat (Miranda et al., 2021)”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Miranda et al., 2021

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AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer’s Disease
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Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease
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Identification and biology of α‐secretase
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The secretion of amyloid β-peptides is inhibited in the tacrine-treated human neuroblastoma cells
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sAPPα antagonizes dendritic degeneration and neuron death triggered by proteasomal stress
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Kuang, X., Zhou, H., Thorne, A. H., Chen, X.-N., Li, L.-J., & Du, J. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00353 · Cited by 74 · see citing works
New evolutions in the BACE1 inhibitor field from 2014 to 2018
Hsiao, C., Rombouts, F. J. R., & Gijsen, H. J. M. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.12.049 · Cited by 74 · see citing works
Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer's disease
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Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches
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Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice
Shimshek, D. R., Jacobson, L. H., Kolly, C., Zamurovic, N., Balavenkatraman, K. K., Morawiec, L., Kreutzer, R., Schelle, J., Jucker, M., Bertschi, B., et al. (2016) · Scientific Reports · doi:10.1038/srep21917 · Cited by 69 · see citing works
The pharmacology of tacrine at N -methyl- d -aspartate receptors
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Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending Dose Study of the Oral γ-Secretase Inhibitor BMS-708163 (Avagacestat): Tolerability Profile, Pharmacokinetic Parameters, and Pharmacodynamic Markers
Tong, G., Wang, J.-S., Sverdlov, O., Huang, S., Slemmon, R., Croop, R. S., Castaneda, L., Gu, H., Wong, O. T., Li, H., et al. (2012) · Clinical Therapeutics · doi:10.1016/j.clinthera.2012.01.022 · Cited by 64 · see citing works
Berberine Alleviates Amyloid-Beta Pathology in the Brain of APP/PS1 Transgenic Mice via Inhibiting β/γ-Secretases Activity and Enhancing α-Secretases
Cai, Z., Wang, C., He, W., & Chen, Y. (2018) · Current Alzheimer Research · doi:10.2174/1567205015666180702105740 · Cited by 63 · see citing works
Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha (sAPPα)
Dar, N., & Glazner, G. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03404-x · Cited by 62 · see citing works
Profiling the dynamics of CSF and plasma Aβ reduction after treatment with JNJ‐54861911, a potent oral BACE inhibitor
Timmers, M., Broeck, B. V., Ramael, S., Slemmon, J., Waepenaert, K. D., Russu, A., Bogert, J., Stieltjes, H., Shaw, L. M. J., Engelborghs, S., et al. (2016) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.08.001 · Cited by 61 · see citing works
Merck ends trial of potential Alzheimer’s drug verubecestat
Hawkes, N. (2017) · BMJ · doi:10.1136/bmj.j845 · Cited by 59 · see citing works
Association of cerebrospinal fluid α‐synuclein with total and phospho‐tau<sub>181</sub> protein concentrations and brain amyloid load in cognitively normal subjective memory complainers stratified by Alzheimer's disease biomarkers
Vergallo, A., Bun, R., Toschi, N., Baldacci, F., Zetterberg, H., Blennow, K., Cavedo, E., Lamari, F., Habert, M., Dubois, B., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.06.3053 · Cited by 59 · see citing works
Identification of disulfiram as a secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks
Reinhardt, S., Stoye, N., Luderer, M., Kiefer, F., Schmitt, U., Lieb, K., & Endres, K. (2018) · Scientific Reports · doi:10.1038/s41598-018-19577-7 · Cited by 58 · see citing works
Disulfiram implantation in alcoholism treatment. A review.
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Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation
O’Neill, B. T., Beck, E. M., Butler, C. R., Nolan, C. E., Gonzales, C., Zhang, L., Doran, S. D., Lapham, K., Buzon, L. M., Dutra, J. K., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00246 · Cited by 43 · see citing works
Alzheimer’s Disease “Non-amyloidogenic” p3 Peptide Revisited: A Case for Amyloid-α
Kuhn, A. J., Abrams, B. S., Knowlton, S., & Raskatov, J. A. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00160 · Cited by 41 · see citing works
Secreted amyloid precursor protein-alpha can restore novel object location memory and hippocampal LTP in aged rats
Xiong, M., Jones, O. D., Peppercorn, K., Ohline, S. M., Tate, W. P., & Abraham, W. C. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.08.002 · Cited by 40 · see citing works
O3-06-07 Multi-compartmental pharmacodynamic assessment of the functional gamma-secretase inhibitor LY450139 in PDAPP transgenic mice and non-transgenic mice
May, P. C., Yang, Z., Li, W., Hyslop, P. A., Siemers, E., & Boggs, L. N. (2004) · Neurobiology of Aging · doi:10.1016/s0197-4580(04)80220-3 · Cited by 39 · see citing works
Cryptotanshinione upregulates α-secretase by activation PI3K pathway in cortical neurons
Mei, Z., Situ, B., Tan, X., Zheng, S., Zhang, F., Yan, P., & Liu, P. (2010) · Brain Research · doi:10.1016/j.brainres.2010.05.083 · Cited by 39 · see citing works
Molecular Signaling Pathways Behind the Biological Effects ofSalviaSpecies Diterpenes in Neuropharmacology and Cardiology
Akaberi, M., Iranshahi, M., & Mehri, S. (2016) · Phytotherapy Research · doi:10.1002/ptr.5599 · Cited by 38 · see citing works
Pharmacokinetic and Pharmacodynamic Effects of a γ‐Secretase Modulator, PF ‐06648671, on CSF Amyloid‐β Peptides in Randomized Phase I Studies
Ahn, J. E., Carrieri, C., Cruz, F. D., Fullerton, T., Hajós‐Korcsok, É., He, P., Kantaridis, C., Leurent, C., Liu, R., Mancuso, J. Y., et al. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1570 · Cited by 38 · see citing works
THE ALZHEIMER’S PREVENTION INITIATIVE GENERATION PROGRAM: EVALUATING CNP520 EFFICACY IN THE PREVENTION OF ALZHEIMER’S DISEASE
López, C. L., Caputo, A., Liu, F., Riviere, M., Rouzade‐Dominguez, M., Thomas, R. G., Langbaum, J. B. S., Lenz, R., Reiman, E. M., Graf, A., et al. (2017) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2017.37 · Cited by 36 · see citing works
P4‐389: ELENBECESTAT, E2609, A BACE INHIBITOR: RESULTS FROM A PHASE‐2 STUDY IN SUBJECTS WITH MILD COGNITIVE IMPAIRMENT AND MILD‐TO‐MODERATE DEMENTIA DUE TO ALZHEIMER'S DISEASE
Lynch, S. Y., Kaplow, J. M., Zhao, J., Dhadda, S., Luthman, J., & Albala, B. (2018) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2018.07.213 · Cited by 35 · see citing works
Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission
Şatır, T. M., Agholme, L., Karlsson, A., Karlsson, M., Karila, P., Illes, S., Bergström, P., & Zetterberg, H. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00635-0 · Cited by 33 · see citing works
BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer’s Disease Markers in Elderly Healthy Participants
Timmers, M., Barão, S., Broeck, B. V., Tesseur, I. C., Slemmon, J., Waepenaert, K. D., Bogert, J., Shaw, L. M. J., Engelborghs, S., Moechars, D., et al. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-160829 · Cited by 32 · see citing works
Aging in Context
Pruchno, R. A. (2017) · The Gerontologist · doi:10.1093/geront/gnx189 · Cited by 30 · see citing works
P4-339 Stereoselective inhibition of amyloid beta peptide secretion by LY450139, a novel functional gamma secretase inhibitor
Gitter, B. D., Czilli, D. L., Li, W., Dieckman, D. K., Bender, M. H., Nissen, J. S., Mabry, T. E., Yin, T., Boggs, L. N., McClure, D. B., et al. (2004) · Neurobiology of Aging · doi:10.1016/s0197-4580(04)81897-9 · Cited by 29 · see citing works
Chronic Verubecestat Treatment Suppresses Amyloid Accumulation in Advanced Aged Tg2576-AβPPswe Mice Without Inducing Microhemorrhage
Villarreal, S. A., Zhao, F., Hyde, L. A., Holder, D., Forest, T. W., Sondey, M., Chen, X., Sur, C., Parker, E. M., & Kennedy, M. E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170056 · Cited by 29 · see citing works
The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects
Neumann, U., Machauer, R., & Shimshek, D. R. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14582 · Cited by 27 · see citing works
The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients
Guilherme, M. D. S., Stoye, N. M., Rose‐John, S., Garbers, C., Fellgiebel, A., & Endres, K. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00182 · Cited by 27 · see citing works
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects
Qiu, R., Ahn, J. E., Alexander, R., Brodney, M. A., He, P., Leurent, C., Mancuso, J. Y., Margolin, R. A., Tankisheva, E., & Chen, D. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190228 · Cited by 27 · see citing works
ADAM9 Mediates Triple-Negative Breast Cancer Progression via AKT/NF-κB Pathway
Zhou, R., Cho, W. C. S., Ma, V. W. S., Cheuk, W., So, Y. K., Wong, S. C. C., Zhang, M., Li, C., Sun, Y., Zhang, H., et al. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00214 · Cited by 26 · see citing works
Pharmacokinetics and Pharmacodynamics of the BACE 1 Inhibitor Verubecestat ( MK ‐8931) in Healthy Japanese Adults: A Randomized, Placebo‐Controlled Study
Min, K. C., Dockendorf, M. F., Palcza, J. S., Tseng, J., Ma, L., Stone, J. A., Kleijn, H. J., Hodsman, P., Masuo, K., Tanen, M., et al. (2018) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1258 · Cited by 24 · see citing works
Stimulation of Non-Amyloidogenic Processing of Amyloid-β Protein Precursor by Cryptotanshinone Involves Activation and Translocation of ADAM10 and PKC-α
Durairajan, S. S. K., Liu, L., Lu, J., Koo, I., Maruyama, K., Chung, S. K., Huang, J., & Li, M. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-102085 · Cited by 23 · see citing works
Two Diterpenes and Three Diterpene Glucosides from Phlogacanthus curviflorus
Yuan, X., Li, B., Zhang, X.-Y., Qi, H., Zhou, M., & Zhang, G. (2004) · Journal of Natural Products · doi:10.1021/np0497999 · Cited by 23 · see citing works
Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer's Disease.
Ratni, H., Alker, A., Bartels, B., Bissantz, C., Chen, W.-C., Gerlach, I., Limberg, A., Lu, M., Neidhart, W. L., Pichereau, S., et al. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00109 · Cited by 22 · see citing works
ESTABLISHING COMPOSITE COGNITIVE ENDPOINTS FOR USE IN PRECLINICAL ALZHEIMER’S DISEASE TRIALS
Langbaum, J. B. S., Hendrix, S. B., Ayutyanont, N., Bennett, D. A., Shah, R. C., Barnes, L. L., Lopera, F. J., Reiman, E. M., & Tariot, P. N. (2015) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2015.46 · Cited by 21 · see citing works
Safety, Tolerability, and Pharmacokinetics of the β‐Site Amyloid Precursor Protein‐Cleaving Enzyme 1 Inhibitor Verubecestat ( MK ‐8931) in Healthy Elderly Male and Female Subjects
Forman, M. S., Palcza, J. S., Tseng, J., Stone, J. A., Walker, B., Swearingen, D., Troyer, M. D., & Dockendorf, M. F. (2019) · Clinical and Translational Science · doi:10.1111/cts.12645 · Cited by 19 · see citing works
Biopsy Pathology and Immunohistochemistry of a Case of Immune‐Mediated Drug‐Induced Liver Injury With Atabecestat
Jonghe, S. D., Weinstock, D., Aligo, J. A., Washington, K., & Naisbitt, D. J. (2020) · Hepatology · doi:10.1002/hep.31403 · Cited by 19 · see citing works
Action of a chronic disulfiram administration on memory decay and on central cholinergic and adrenergic systems
Molinengo, L., Oggero, L., Ghi, P., & Orsetti, M. (1991) · Brain Research · doi:10.1016/0006-8993(91)90915-i · Cited by 18 · see citing works
Quantitative interaction proteomics reveals differences in the interactomes of amyloid precursor protein isoforms
Andrew, R. J., Fisher, K., Heesom, K. J., Kellett, K. A. B., & Hooper, N. M. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14666 · Cited by 16 · see citing works
What We Learn from the CTAD 2018 (Clinical Trials Alzheimer's Disease)
Vellas, B. J., Aisen, P. S. S., Weiner, M. W., & Touchon, J. (2018) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2017.38 · Cited by 15 · see citing works
Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety
Sekioka, R., Honjo, E., Honda, S., Fuji, H., Akashiba, H., Mitani, Y., & Yamasaki, S. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.11.049 · Cited by 15 · see citing works
Optimization and biological evaluation of imidazopyridine derivatives as a novel scaffold for γ-secretase modulators with oral efficacy against cognitive deficits in Alzheimer’s disease model mice
Sekioka, R., Honda, S., Akashiba, H., Yarimizu, J., Mitani, Y., & Yamasaki, S. (2020) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2020.115455 · Cited by 15 · see citing works
Identification of Phlogacantholide C as a Novel ADAM10 Enhancer from Traditional Chinese Medicinal Plants
Meineck, M., Schuck, F., Abdelfatah, S., Efferth, T., & Endres, K. (2016) · Medicines · doi:10.3390/medicines3040030 · Cited by 12 · see citing works
Mechanisms that synergistically regulate η-secretase processing of APP and Aη-α protein levels: relevance to pathogenesis and treatment of Alzheimer's disease.
Ward, J. F., Wang, H., Saunders, A. J., Tanzi, R. E., & Zhang, C. M. (2017) · PubMed · Cited by 11 · see citing works
[P3–037]: PRECLINICAL STUDIES WITH ELENBECESTAT, A NOVEL BACE1 INHIBITOR, SHOW NO EVIDENCE OF HYPOPIGMENTATION
Moriyama, T., Fukushima, T., Kokate, T. G., & Albala, B. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.06.1850 · Cited by 8 · see citing works
Discovery of N-ethylpyridine-2-carboxamide derivatives as a novel scaffold for orally active γ-secretase modulators
Sekioka, R., Honda, S., Honjo, E., Suzuki, T., Akashiba, H., Mitani, Y., & Yamasaki, S. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.115132 · Cited by 8 · see citing works
Inhibition Mechanism of Rat α3β4Nicotinic Acetylcholine Receptor by the Alzheimer Therapeutic Tacrine
Cheffer, A., & Ulrich, H. (2011) · Biochemistry · doi:10.1021/bi101789y · Cited by 7 · see citing works
[P1–043]: ELENBECESTAT, A NOVEL ORAL BACE INHIBITOR, HAS NO CLINICALLY MEANINGFUL EFFECT ON QTC INTERVAL UP TO A SUPRATHERAPEUTIC DOSE OF 200 MG
Lai, R. Y. K., Darpö, B., Dayal, S., Hall, N., Chang, M., Albala, B., Ferry, J., & Rege, B. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.06.110 · Cited by 7 · see citing works
Caspr1 Facilitates sAPPα Production by Regulating α-Secretase ADAM9 in Brain Endothelial Cells
Tang, S., Liu, D.-X., Li, Y., Wang, K., Wang, X.-F., Su, Z.-K., Fang, W.-G., Qin, X.-X., Wei, J.-Y., Zhao, W.-D., et al. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00023 · Cited by 6 · see citing works
P2‐009: PF‐06648671–A Novel Gamma Secretase Modulator: Safety, Tolerability, Pharmacokinetics, and Effects on Plasma Amyloid‐B Levels Following Single Oral Ascending Doses in Healthy Volunteers
Qiu, R., Liu, R., Wills, A.-M. A., He, P., Leurent, C., Hajós‐Korcsok, É., da Costa, L. M., & Alexander, R. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.1213 · Cited by 5 · see citing works
[P1–042]: PLASMA PHARMACOKINETICS AND PHARMACODYNAMICS OF SOLANEZUMAB IN MILD AND MODERATE AD PATIENTS
Willis, B. A., Ferguson‐Sells, L. R., Chua, L., Siemers, E., Dean, R. A., Lachno, D. R., Carlson, C. D., Hake, A. M., Hoffmann, V. P., & Friedrich, S. W. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.06.109 · Cited by 5 · see citing works
FTS3‐01‐01: UMIBECESTAT (CNP520) IS NOT ASSOCIATED WITH CHANGES IN HIPPOCAMPAL MORPHOLOGY IN RATS OR CHANGES IN CSF AD BIOMARKERS IN HUMANS TREATED FOR 3 MONTHS
Graf, A., Kolly, C., Dubost, V., Vassar, R. J., Portelius, E., Höglund, K., Blennow, K., Rouzade‐Dominguez, M., Pezous, N., Kretz, S., et al. (2019) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2019.06.4618 · Cited by 2 · see citing works
P2‐008: MRI Findings Determine Two Clinical Subtypes of Patients with Cerebral Amyloid Angiopathy‐Related Inflammation
Kasuga, K., Ishiguro, T., Tokutake, T., Nishizawa, M., & Ikeuchi, T. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2016.06.1212 · Cited by 1 · see citing works

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Role of Nrf2 in aging, Alzheimer’s and other neurodegenerative diseases
George, M., Tharakan, M., Culberson, J. W., Reddy, A. P., & Reddy, P. H. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101756 · Cited by 212 · see citing works
Novel Therapeutic Approaches for Alzheimer’s Disease: An Updated Review
Yu, T.-W., Lane, H., & Lin, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158208 · Cited by 182 · see citing works
Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks
Peng, Y., Jin, H., Xue, Y.-H., Chen, Q., Yao, S., Du, M., & Liu, S. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1206572 · Cited by 176 · see citing works
The role of PI3K signaling pathway in Alzheimer’s disease
Pan, J., Yao, Q., Wang, Y., Chang, S., Li, C., Wu, Y., Shen, J., & Yang, R. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1459025 · Cited by 89 · see citing works
Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes
Piccialli, I., Tedeschi, V., Caputo, L., D’Errico, S., Ciccone, R., De Feo, V., Secondo, A., & Pannaccione, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.876614 · Cited by 73 · see citing works
Alzheimer’s disease clinical trial update 2019–2021
Pleen, J., & Townley, R. A. (2021) · Journal of Neurology · doi:10.1007/s00415-021-10790-5 · Cited by 68 · see citing works
Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
Thawabteh, A. M., Ghanem, A. W., AbuMadi, S., Thaher, D., Jaghama, W., Karaman, D., & Karaman, R. (2024) · Molecules · doi:10.3390/molecules29215131 · Cited by 56 · see citing works
“This includes γ -secretase inhibitors, such as tarenflurbil ( 7 , Figure 5) [155,156], avagacestat (labeled as 6 , Figure 5) [157,158], and semagacestat ( 5 , Figure 5) [159,160].”
Background
Recent advancements in the therapeutic approaches for Alzheimer's disease treatment: current and future perspective
Sharma, A., Rudrawar, S., Bharate, S. B., & Jadhav, H. R. (2024) · RSC Medicinal Chemistry · doi:10.1039/d4md00630e · Cited by 52 · see citing works
miR-30a-5p induces Aβ production via inhibiting the nonamyloidogenic pathway in Alzheimer’s disease
Sun, T., Zhao, K., Liu, M., Cai, Z., Zeng, L., Zhang, J., Li, Z., & Liu, R. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106153 · Cited by 49 · see citing works
Research progress of natural products and their derivatives against Alzheimer’s disease
Liu, J., Guo, H., Quan, Z., Shen, Q., Cui, H., & Li, X. (2023) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2023.2171026 · Cited by 36 · see citing works
Reducing PDK1/Akt Activity: An Effective Therapeutic Target in the Treatment of Alzheimer’s Disease
Yang, S., Du, Y., Zhao, X., Wu, C., & Yu, P. (2022) · Cells · doi:10.3390/cells11111735 · Cited by 36 · see citing works
LncRNAs as the Regulators of Brain Function and Therapeutic Targets for Alzheimer’s Disease
Liu, Y., Chen, X., Che, Y., Li, H., Zhang, Z., Peng, W., & Yang, J. (2022) · Aging and Disease · doi:10.14336/ad.2021.1119 · Cited by 35 · see citing works
Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease
Chen, J., Chen, J.-S., Li, S., Zhang, F., Deng, J., Zeng, L., & Tan, J. (2023) · Aging and Disease · doi:10.14336/ad.2023.0308 · Cited by 30 · see citing works
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Authors: Miranda, A., Montiel, E., Ulrich, H., & Paz, C.
Affiliations: Universidad de La Frontera (CL)
Universidade de São Paulo (BR)
Corresponding author: Ulrich, Henning
Paz, Cristian
ORCID: Ulrich, Henning
Paz, Cristian
Venue: Journal of Alzheimer s Disease
Publisher: SAGE Publications
Published: 2021-05-04
Volume: 81
Issue: 1
Pages: 1-17
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-201027
OpenAlex: W3138418840
Cited by: 66
References: 130
Citations by year: 2026: 8 · 2025: 9 · 2024: 17 · 2023: 14 · 2022: 12 · 2021: 6
FWCI: 1.63
Type: journal article
Language: en
Open access: green
repositorio.ufro.cl
Licence: cc-by-nc-nd
Locations: Journal of Alzheimer s Disease (publishedVersion)
PubMed (publishedVersion)
Omeka S (Universidad de La Frontera) (submittedVersion, cc-by-nc-nd)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, secretase inhibitors
MeSH terms: Alzheimer Disease, Animals, Humans, Neuroprotective Agents, Amyloid Precursor Protein Secretases

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Selective Secretase Targeting for Alzheimer’s Disease Therapy

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