Cited by 300Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

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McConlogue, Lisa, Buttini, Manuel, Anderson, John P., Brigham, Elizabeth F., Chen, Karen S., Freedman, Stephen B., Games, Dora, Johnson-Wood, Kelly, Lee, Michael, Zeller, Michelle, Liu, Weiqun, Motter, Ruth, Sinha, Sukanto·2007·Journal of Biological Chemistry

DOI 10.1074/jbc.m611687200

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Abstract

The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates processing of amyloid precursor protein (APP) into amyloid beta (Abeta) peptide, the major component of Alzheimer disease (AD) plaques. To determine the role that BACE1 plays in the development of Abeta-driven AD-like pathology, we have crossed PDAPP mice, a transgenic mouse model of AD overexpressing human mutated APP, onto mice with either a homozygous or heterozygous BACE1 gene knockout. Analysis of PDAPP/BACE(-/-) mice demonstrated that BACE1 is absolutely required for both Abeta generation and the development of age-associated plaque pathology. Furthermore, synaptic deficits, a neurodegenerative pathology characteristic of AD, were also reversed in the bigenic mice. To determine the extent of BACE1 reduction required to significantly inhibit pathology, PDAPP mice having a heterozygous BACE1 gene knock-out were evaluated for Abeta generation and for the development of pathology. Although the 50% reduction in BACE1 enzyme levels caused only a 12% decrease in Abeta levels in young mice, it nonetheless resulted in a dramatic reduction in Abeta plaques, neuritic burden, and synaptic deficits in older mice. Quantitative analyses indicate that brain Abeta levels in young APP transgenic mice are not the sole determinant for the changes in plaque pathology mediated by reduced BACE1. These observations demonstrate that partial reductions of BACE1 enzyme activity and concomitant Abeta leve…

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Shi, Q., Prior, M., He, W., Tang, X., Hu, X., & Yan, R. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.5741-08.2009 · Cited by 59
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Elevation of Brain Magnesium Prevents and Reverses Cognitive Deficits and Synaptic Loss in Alzheimer's Disease Mouse Model
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Background
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“the partial inhibition of BACE1 results in reduced total amyloid-b levels, whereas amyloid-b42 levels remain unchanged (McConlogue et al., 2007).”
Background
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Background
Inhibitory Evaluation of Sulfonamide Chalcones on β-Secretase and Acylcholinesterase
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“BACE1 is uniquely able to process APP and thus form Aβ-peptides, because BACE1 knock-out mice are unable to form Aβ peptides [12].”
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BackgroundResultInfluential
AZ-4217: A High Potency BACE Inhibitor Displaying Acute Central Efficacy in Different In Vivo Models and Reduced Amyloid Deposition in Tg2576 Mice
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Background
Acyl guanidine inhibitors of β-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.
Gerritz, S., Zhai, W., Shi, S., Zhu, S., Toyn, J., Meredith, J., Iben, L., Burton, C., Albright, C., Good, A., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300931y · Cited by 45
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Sheline, Y. I., Snider, B. J., Beer, J. C., Seok, D., Fagan, A. M., Suckow, R. F., Lee, J.-M., Waligorska, T., Korecka, M., Aselcioglu, I., et al. (2020) · Neurology · doi:10.1212/wnl.0000000000010725 · Cited by 45
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“A previous study of BACE1 heterozygote mice overexpressing mutant human APP platelet-derived growth factor promoter (PDAPP;BACE1+/−) showed a considerable reduction in brain Aβ levels and plaque load without side effect [10].”
Background
Physical activity and beta-amyloid pathology in Alzheimer's disease
Ebrahimi, K., Majdi, A., Baghaiee, B., Hosseini, S. H., & Sadigh‐Eteghad, S. (2017) · EXCLI journal · doi:10.17179/excli2017-475 · Cited by 42
“…AD Treadmill exercise 12-week Reversing cognitive decline Decrease in the Aβ and p-tau levels - Modulation of PSD-95, synaptophysin and BDNF levels (McConlogue et al., 2007) PS2 mutant mice AD Treadmill exercise 12-week Improvement of spatial learning and memory Reduction of Aβ42 through…”
BackgroundMethodInfluential
Alzheimer’s therapy targeting the β-secretase enzyme BACE1: Benefits and potential limitations from the perspective of animal model studies
Ohno, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.04.007 · Cited by 50
IGF-1 Reduces BACE-1 Expression in PC12 Cells via Activation of PI3-K/Akt and MAPK/ERK1/2 Signaling Pathways
Zhang, H., Gao, Y., Dai, Z.-W., Meng, T., Tu, S.-F., & Yan, Y. (2010) · Neurochemical Research · doi:10.1007/s11064-010-0260-x · Cited by 42
“and cognitive dysfunction in AD models [7, 8].”
Interplay Between Vascular Dysfunction and Neurodegenerative Pathology: New Insights into Molecular Mechanisms and Management
Mekala, A., & Qiu, H. (2025) · Biomolecules · doi:10.3390/biom15050712 · Cited by 49
“Using this antibody transport vehicle (ATV), researchers have successfully delivered anti-BACE1 (Beta-site APP Cleaving Enzyme 1) antibodies in APP (amyloid precursor protein) transgenic mice, resulting in reduced A β levels and plaque formation [91–93].”
The neurobiology and therapeutic potential of multi-targeting β-secretase, glycogen synthase kinase 3β and acetylcholinesterase in Alzheimer’s disease
Fronza, M. G., Alves, D. A. C., Praticò, D., & Savegnago, L. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102033 · Cited by 47
Pharmacogenetic features of cathepsin B inhibitors that improve memory deficit and reduce β-amyloid related to Alzheimer's disease
HOOK, V. Y. H., Hook, G., & Kindy, M. S. (2010) · Biological Chemistry · doi:10.1515/bc.2010.110 · Cited by 46
“Another study showed that at super high levels of APP expression in transgenic mice, BACE1 gene knockout resulted in decreased brain Ab levels (McConlogue et al., 2007).”
Background
Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1
Cole, S. L., & Vassar, R. J. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.12.012 · Cited by 38
Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease
Zuliani, G., Trentini, A., Rosta, V., Guerrini, R., Pacifico, S., Bonazzi, S., Guiotto, A., Passaro, A., Seripa, D., Valacchi, G., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-72168-3 · Cited by 42
Bridging the Gap Between Fluid Biomarkers for Alzheimer’s Disease, Model Systems, and Patients
Bjorkli, C., Sandvig, A., & Sandvig, I. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00272 · Cited by 41
MiR-361-3p inhibits β-amyloid accumulation and attenuates cognitive deficits through targeting BACE1 in Alzheimer's disease
Ji, Y., Wang, D., Zhang, B., & Lu, H. (2019) · Journal of Integrative Neuroscience · doi:10.31083/j.jin.2019.03.1136 · Cited by 40
“It was reported that modest rather than full inhibition of Aβ in AD patients could lead to a reduction of pathology (Carney, 2018; McConlogue et al., 2007).”
Background
The Resveratrol Trimer Miyabenol C Inhibits β-Secretase Activity and β-Amyloid Generation
Hu, J., Lin, T., Gao, Y., Xu, J., Jiang, C., Wang, G., Bu, G., Xu, H., Chen, H., & Zhang, Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0115973 · Cited by 44
“Although homozygous BACE1 knock-out mice develop certain phenotypic abnormalities including reduced body size, hyperactive behavior, decreased grip strength and elevated pain sensitivity [12–14], probably because the cleavage of other BACE1 substrates such as neuregulin 1 [13, 14] and β-subunits of voltage-gated sodiu…”
Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer’s disease
van Tijn, P., Dennissen, F. J. A., Gentier, R. J. G., Hobo, B., Hermes, D., Steinbusch, H. W. M., Van Leeuwen, F. W., & Fischer, D. F. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.07.007 · Cited by 39
DNA methylation in the pathology of Alzheimer's disease: from gene to cognition
Poon, C. H., Tse, L. S. R., & Lim, L. W. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14373 · Cited by 47
Interpreting Alzheimer’s disease clinical trials in light of the effects on amyloid-β
Toyn, J. H., & Ahlijanian, M. K. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt244 · Cited by 31
“BACE1 knock out (KO) mice exhibited a range of Aβ lowering from 12% for heterozygous to >90% for homozygous animals, with cognitive benefits in multiple types of cognitive assays [14-20].”
Background
Mechanisms that lessen benefits of β-secretase reduction in a mouse model of Alzheimer’s disease
Devi, L., & Ohno, M. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.59 · Cited by 38
“This is in agreement with the previous findings that BACE1 haploinsufficiency can reduce Ab concentrations and plaque load during earlier stages of progressive AD-like pathology, whereas it has little or no effects on robust b-amyloidosis at later stages in different APP transgenic mice.(11,22) Our results further rev…”
BackgroundResult
Structure-Based Design of an Iminoheterocyclic β-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates.
Mandal, M., Wu, Y.-S., Misiaszek, J., Li, G.-Q., Buevich, A., Caldwell, J., Liu, X.-X., Mazzola, R., Orth, P., Strickland, C., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01995 · Cited by 37
Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses
Lu, Y., Riddell, D. R., Hajós‐Korcsok, É., Bales, K. R., Wood, K. M., Nolan, C. E., Robshaw, A., Zhang, L., Leung, L. Y., Becker, S. L., et al. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.192625 · Cited by 35
“brain A level at 3 months of age led to a dramatic inhibition in A deposition and neuritic dystrophy over time (McConlogue et al., 2007).”
Background
The Mitochondrial Secret(ase) of Alzheimer's Disease
Young, K. J., & Bennett, J. P. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100360 · Cited by 34
“In accordance with the amyloid cascade hypothesis, homogeneous and heterogeneous BACE1 knockouts eliminate or reduce Aβ generation, decrease plaque formation, and improve synaptic plasticity and memory of transgenic AD mice [56] [57] [58].”
Background
Allosteric inhibition of BACE1 by an exosite-binding antibody
Wang, W., Liu, Y., & Lazarus, R. A. (2013) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2013.08.001 · Cited by 37
Heparan Sulfate Proteoglycans in Amyloidosis
Zhang, X. L., & Li, J. (2010) · Progress in molecular biology and translational science · doi:10.1016/s1877-1173(10)93013-5 · Cited by 41
The Identification of Biochanin A as a Potent and Selective β-Site App-Cleaving Enzyme 1 (Bace1) Inhibitor
Youn, K., Park, J., Lee, J., Jeong, W., Ho, C.-T., & Jun, M. (2016) · Nutrients · doi:10.3390/nu8100637 · Cited by 34
A combination Alzheimer’s therapy targeting BACE1 and neprilysin in 5XFAD transgenic mice
Devi, L., & Ohno, M. (2015) · Molecular Brain · doi:10.1186/s13041-015-0110-5 · Cited by 37
“, a therapeutic relevant model for 50% suppression) [12-18] as well as chronic treatments with bioavailable small-molecule BACE1 inhibitors (e.”
Background
Discovery of 7-tetrahydropyran-2-yl chromans: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid β-protein (Aβ) in the central nervous system.
Thomas, A. A., Hunt, K. W., Volgraf, M., Watts, R., Liu, X.-R., Vigers, G., Smith, D. J., Sammond, D., Tang, T. P., Rhodes, S., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401635n · Cited by 34
BACE1 Inhibitors for Alzheimer’s Disease: Current Challenges and Future Perspectives
Coimbra, J. R. M., Resende, R., Custódio, J. B. A., Salvador, J. A. R., & Santos, A. E. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240146 · Cited by 43
“Nonetheless, preclinical studies with AD animal models, including our own work, point that a partial reduction of BACE1 enzyme activity throughout the time leads to a dramatic decrease in insoluble A (cid:2) levels [97], amyloid plaque deposition and synaptic pathology [98].”
BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice
Kim, W., Ma, L., Lomoio, S., Willen, R., Lombardo, S., Dong, J., Haydon, P. G., & Tesco, G. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0239-7 · Cited by 32
“[25] reported a decrease in Aβ42 levels but no change in sAPPβ in 13 month-old BACE1Het;PDAPP mice.”
BACE1 inhibition as a therapeutic strategy for Alzheimer's disease
Vassar, R. (2014) · Journal of Sport and Health Science · doi:10.1016/j.jshs.2016.10.004 · Cited by 30
The Synaptic Vesicle Protein 2A Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment
Kong, Y., Huang, L., Li, W., Liu, X., Zhou, Y., Liu, C., Zhang, S., Xie, F., Zhang, Z., Jiang, D., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.609908 · Cited by 29
Soluble BACE-1 Activity and sAβPPβ Concentrations in Alzheimer’s Disease and Age-Matched Healthy Control Cerebrospinal Fluid from the Alzheimer’s Disease Neuroimaging Initiative-1 Baseline Cohort
Savage, M. J., Holder, D., Wu, G., Kaplow, J. M., Siuciak, J. A., & Potter, W. Z. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-142778 · Cited by 28
“This is consistent with findings in heterozygous BACE1 knockout mice with 50% reduced BACE1 activity which do not have reduced A ; complete gene knockout was required to change A concentrations [36].”
Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents.
Sealy, J., Truong, A. P., Tso, L. S., Probst, G., Aquino, J., Hom, R. K., Jagodzinska, B. M., Dressen, D., Wone, D. W. G., Brogley, L., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.09.061 · Cited by 29
Self-citation
Constitutive JAK2/STAT1 activation regulates endogenous BACE1 expression in neurons.
Cho, H., Jin, S., Son, S., Kim, Y. W., Hwang, J.-Y., Hong, H., & Mook-Jung, I. (2009) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2009.06.006 · Cited by 29
Translational Medicine Lessons from Flurizan's Failure in Alzheimer's Disease (AD) Trial: Implication for Future Drug Discovery and Development for AD
Wan, H. I., Jacobsen, J., Rutkowski, J., & Feuerstein, G. (2009) · Clinical and Translational Science · doi:10.1111/j.1752-8062.2009.00121.x · Cited by 29
Beneficial Effects of the β-Secretase Inhibitor GRL-8234 in 5XFAD Alzheimer’s Transgenic Mice Lessen During Disease Progression
Devi, L., Tang, J., & Ohno, M. (2015) · Current Alzheimer Research · doi:10.2174/1567205012666141218125042 · Cited by 28
“However, it should be noted that the beneficial effects of BACE1 haploinsufficiency in AD transgenic mice dramatically decline with age or the progression of disease [13, 16, 17, 19].”
Background
BACE1: A Key Regulator in Alzheimer’s Disease Progression and Current Development of its Inhibitors
Patel, S., Bansoad, A. V., Singh, R., & Khatik, G. L. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666211201094031 · Cited by 69
“Reducing cellular Aβ peptides by around 20% is preventative for AD if commenced before significant Aβ accumulation [107, 108].”
Effects of BACE1 Haploinsufficiency on APP Processing and Aβ Concentrations in Male and Female 5XFAD Alzheimer Mice at Different Disease Stages
Devi, L., & Ohno, M. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.08.037 · Cited by 28
“…and siRNA) reduces Aβ/C99 levels and mitigates ADlike pathologies and memory impairments in transgenic mouse models (Singer et al., 2005, McConlogue et al., 2007, Devi and Ohno, 2010a, Devi and Ohno, 2010b, Kimura et al., 2010, Chabrier et al., 2012, Devi and Ohno, 2012, Devi and Ohno,…”
Background
The Swedish APP mutation alters the effect of genetically reduced BACE1 expression on the APP processing
Rabe, S., Reichwald, J., Ammaturo, D., Strooper, B. D., Säftig, P., Neumann, U., & Staufenbiel, M. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07412.x · Cited by 28
“2004), a 12% (McConlogue et al. 2007) or 20% decrease (Sankaranarayanan et al.”
BackgroundInfluential
Genetic pathway‐based hierarchical clustering analysis of older adults with cognitive complaints and amnestic mild cognitive impairment using clinical and neuroimaging phenotypes
Sloan, C., Shen, L., West, J. D., Wishart, H. A., Flashman, L. A., Rabin, L. A., Santulli, R. B., Guerin, S. J., Rhodes, C. H., Tsongalis, G. J., et al. (2010) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31078 · Cited by 28
“…cleavage and translocation [Miller et al., 2006; Ho et al., 2008; Saito et al., 2008] (also known as MINT1, X11) BACE1 Cleaves APP [Haass, 2004; McConlogue et al., 2007; Willem et al., 2009] BACE2 Cleaves APP, a BACE1 homolog [Stockley and O’Neill, 2007], increases IL-1R2 secretion [Kuhn et…”
Background
Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport
Ruderisch, N., Schlatter, D., Kuglstatter, A., Guba, W., Huber, S., Cusulin, C., Benz, J., Rufer, A. C., Hoernschemeyer, J., Schweitzer, C., et al. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.09.004 · Cited by 30
Differential contributions of ApoE4 and female sex to BACE1 activity and expression mediate Aβ deposition and learning and memory in mouse models of Alzheimer’s disease
Hou, X., Adeosun, S. O., Zhang, Q., Barlow, B., Brents, M., Zheng, B., & Wang, J. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00207 · Cited by 25
MAM and C99, key players in the pathogenesis of Alzheimer’s disease
Pera, M., Montesinos, J., Larrea, D., Agrawal, R. R., VELASCO, K. R., Stavrovskaya, I. G., Yun, T. D., & Área-Gómez, E. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.016 · Cited by 35
Cellular Targeting of Oligonucleotides by Conjugation with Small Molecules
Hawner, M., & Ducho, C. (2020) · Molecules · doi:10.3390/molecules25245963 · Cited by 31
“This might also have an impact on the development of drugs against Alzheimer’s disease [402,403].”
Background
Prospects of β-Secretase Inhibitors for the Treatment of Alzheimer’s Disease
Ghosh, A. K., & Tang, J. J. N. (2015) · ChemMedChem · doi:10.1002/cmdc.201500216 · Cited by 25
Bioinformatics Identification of Modules of Transcription Factor Binding Sites in Alzheimer′s Disease‐Related Genes by In Silico Promoter Analysis and Microarrays
Augustin, R., Lichtenthaler, S. F., Greeff, M., Hansen, J., Wurst, W., & Trümbach, D. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/154325 · Cited by 23
“Additionally, SYP deficits correlate with levels of soluble Aβ, and the loss of the associated presynaptic protein SYP is a key pathological feature of AD [57].”
Background
Electroacupuncture Mitigates Hippocampal Cognitive Impairments by Reducing BACE1 Deposition and Activating PKA in APP/PS1 Double Transgenic Mice
Tang, Y., Shao, S., Guo, Y., Zhou, Y., Cao, J., Xu, A., Wu, J., Li, Z., & Xiang, D. (2019) · Neural Plasticity · doi:10.1155/2019/2823679 · Cited by 29
“The administration of BACE1 inhibitor could dramatically decrease the Aβ level and attenuate behavioral deficits in APP transgenic mice [12, 19], yet their brains naturally possess high concentrations of soluble Aβ.”
Background
Ameliorative effects of a non-competitive BACE1 inhibitor TAK-070 on Aβ peptide levels and impaired learning behavior in aged rats
Takahashi, H., Fukumoto, H., Maeda, R., Terauchi, J., Kato, K., & Miyamoto, M. (2010) · Brain Research · doi:10.1016/j.brainres.2010.09.032 · Cited by 21
Assessing Neuroprotective Agents for Aβ-Induced Neurotoxicity
Forest, K. H., & Nichols, R. A. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.05.013 · Cited by 19
siRNA delivery using polyelectrolyte-gold nanoassemblies in neuronal cells for BACE1 gene silencing
Chaudhary, A., & Garg, S. (2017) · Materials Science and Engineering C · doi:10.1016/j.msec.2017.05.101 · Cited by 25
AβPP-Selective BACE Inhibitors (ASBI): Novel Class of Therapeutic Agents for Alzheimer’s Disease
Descamps, O., Spilman, P., Zhang, Q., Libeu, C. P., Poksay, K., Gorostiza, O. F., Campagna, J. J., Jagodzinska, B., Bredesen, D., & John, V. (2013) · Journal of Alzheimer's Disease · doi:10.3233/jad-130578 · Cited by 22
Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents.
Truong, A. P., Probst, G., Aquino, J., Fang, L., Brogley, L., Sealy, J., Hom, R. K., Tucker, J., John, V., Tung, J., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.06.112 · Cited by 22
Self-citation
High-level expression of a human β-site APP cleaving enzyme in transgenic tobacco chloroplasts and its immunogenicity in mice
Youm, J., Jeon, J., Kim, H., Min, S., Kim, M. S., Joung, H., Jeong, W.-J., & Kim, H. S. (2010) · Transgenic research · doi:10.1007/s11248-010-9383-8 · Cited by 22
“Therefore, b-secretase inhibition through vaccination is presently receiving increased attention worldwide (McConlogue et al. 2007).”
Background
Circulating Small Extracellular Vesicle-Derived miR-342-5p Ameliorates Beta-Amyloid Formation via Targeting Beta-site APP Cleaving Enzyme 1 in Alzheimer’s Disease
Dong, Z.-W., Gu, H., Guo, Q., Liu, X., Li, F.-F., Liu, H., Sun, L., Ma, H.-M., & Zhao, K. (2022) · Cells · doi:10.3390/cells11233830 · Cited by 20
“Partial reduction of BACE1 led to only a 12% decrease in Aβ level, obvious reduction of Aβ deposition, and synaptic deficits in a transgenic mouse AD model overexpressing human mutated APP [17].”
Background
Post-Translational Modifications of BACE1 in Alzheimer's Disease
Wen, W., Li, P., Liu, P., Xu, S., Wang, F., & Huang, J. H. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210121163224 · Cited by 33
“One study reported that BACE1 knockout mice showed a 12% decrease in Aβ level in young 5XFAD APP/PS1 mice, and did not show any major behavioral, morphological, or developmental deficit [54, 55].”
Background
The inhibitory effect of chitosan oligosaccharides on β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in HEK293 APPswe cells.
Dai, X., Chang, P., Li, X.-X., Gao, Z., & Sun, Y.-X. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2017.11.052 · Cited by 20
Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: Conformational analysis and binding mode of multisite inhibitors
Pietro, O. D., Juárez-Jiménez, J., Muñoz-Torrero, D., Laughton, C., & Luque, F. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177683 · Cited by 20
“mice [2-5] suggest that BACE-1 may be a prime biological target for a diseasemodifying therapeutic approach in AD [6-8].”
Background
Oxygen-glucose deprivation regulates BACE1 expression through induction of autophagy in Neuro-2a/APP695 cells
Chen, R., Zhang, T., Sun, Y.-Y., Sun, Y.-M., Chen, W., Shi, N., Shen, F., Zhang, Y., Liu, K.-Y., & Sun, X.-J. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.165511 · Cited by 20
“Thus, BACE1 becomes one of the effective targets for reducing Aβ generation (Ohno et al., 2004, 2007; Laird et al., 2005; McConlogue et al., 2007).”
Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processing
Liu, X.-R., Wong, H., Scearce-Levie, K., Watts, R., Coraggio, M., Shin, Y., Peng, K., Wildsmith, K. R., Atwal, J., Mango, J., et al. (2013) · Drug Metabolism And Disposition · doi:10.1124/dmd.112.050864 · Cited by 20
“through the nonamyloidogenic pathway (McConlogue et al., 2007; Citron, 2010).”
Background
Identification of a small molecule beta-secretase inhibitor that binds without catalytic aspartate engagement.
Steele, T., Hills, I. D., Nomland, A., de León, P., Allison, T., McGaughey, G., Colussi, D., Tugusheva, K., Haugabook, S., Espeseth, A. S., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.11.027 · Cited by 20
DNA Aptamers Targeting BACE1 Reduce Amyloid Levels and Rescue Neuronal Deficiency in Cultured Cells
Xiang, J. Y., Zhang, W., Cai, X., Cai, M., Yu, Z., Yang, F., Zhu, W., Li, X., Wu, T., Zhang, J.-S., et al. (2019) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2019.02.025 · Cited by 23
“In this study, we used cell-SELEX strategy24 to select specific DNA aptamers targeting BACE1.”
BackgroundInfluential
Therapeutic Interventions Targeting Beta Amyloid Pathogenesis in an Aging Dog Model
Martin, S. B., Dowling, A. L. S., & Head, E. (2011) · Current Neuropharmacology · doi:10.2174/157015911798376217 · Cited by 19
“, found decreased A burden in 13 and 18 month old BACE1 +/APP transgenic mice [103].”
Background
Structure-guided design and synthesis of P1' position 1-phenylcycloalkylamine-derived pentapeptidic BACE1 inhibitors.
Tagad, H. D., Hamada, Y., Nguyen, J., Hidaka, K., Hamada, T., Sohma, Y., Kimura, T., & Kiso, Y. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.07.002 · Cited by 19
Combination Therapy in Alzheimer’s Disease: Is It Time?
Salehipour, A., Bagheri, M., Sabahi, M., Dolatshahi, M., & Boche, D. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-215680 · Cited by 22
“It has resulted in reduced A (cid:2) levels and its accumulation into plaques in APP transgenic mice via anti-BACE1 antibodies or acting against tau pathology in tau transgenic mice using anti-tau antibodies [158, 159].”
APP transgenic mice and their application to drug discovery.
Howlett, D. R. (2011) · Histology and Histopathology · doi:10.14670/hh-26.1611 · Cited by 18
“Interestingly, a PDAPP x BACE(+/-) cross demonstrated only a 12% decrease in Aß load in young animals but a dramatic loss of the pathological features of PDAPPs in older mice (McConlogue et al., 2007).”
Background
APOE4-driven lipid metabolic dysregulation in Alzheimer's disease: Multi-pathway mechanisms and therapeutic perspectives
Zhang, W.-X., Yang, Y.-L., Yu, J., Jia, L., & Huang, H. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152335 · Cited by 19
From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects
Pont, C., Ginex, T., Griñán‐Ferré, C., Scheiner, M., Mattellone, A., Martínez, N., Arce, E. M., Soriano-Fernández, Y., Naldi, M., Simone, A. D., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113779 · Cited by 20
“Because BACE-1 can cleave other substrates apart from APP, excessive inhibition of BACE-1 has been proposed to likely account for toxicity issues observed with previous drug candidates, whereas lower levels of inhibition could lead to the desired therapeutic efficacy [23].”
Background

Authors: McConlogue, L., Buttini, M., Anderson, J. P., Brigham, E. F., Chen, K. S., Freedman, S. B., Games, D., Johnson-Wood, K., Lee, M., Zeller, M., Liu, W., Motter, R., & Sinha, S.
Affiliations: Elan Pharmaceuticals, Inc. (Ireland) (IE)
Corresponding author: McConlogue, Lisa
ORCID: McConlogue, Lisa
Buttini, Manuel
Chen, Karen S.
Freedman, Stephen B.
Lee, Michael
Zeller, Michelle
Liu, Weiqun
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2007-09
Volume: 282
Issue: 36
Pages: 26326-26334
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m611687200
OpenAlex: W2000536660
Cited by: 300
References: 56
Citations by year: 2026: 4 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 18 · 2019: 16 · 2018: 13 · 2017: 17 · 2016: 18 · 2015: 24 · 2014: 24 · 2013: 17 · 2012: 23
FWCI: 14.91
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4774 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: BACE1, Alzheimer's disease, amyloid-beta, amyloid plaques, APP transgenic mice, PDAPP mice, synaptic deficits, neuritic plaques, therapeutic target
MeSH terms: Aging, Alzheimer Disease, Animals, Disease Models, Animal, Enzyme Activation, Humans, Synaptic Membranes, Aspartic Acid Endopeptidases, Neurites, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases

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Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice

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