Partial Reduction of BACE1 Has Dramatic Effects on Alzheimer Plaque and Synaptic Pathology in APP Transgenic Mice
Open accessAbstract
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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Inhibition of BACE1 by RNAi-mediated knock-down or genetic deletion ameliorates Aβ-associated pathologies and cognitive deficits in mouse models of Aβ-amyloidosis.
“In fact, several studies unequivocally demonstrated that inhibition of BACE1 by RNAi-mediated knock-down or genetic deletion ameliorates Aβ-associated pathologies and cognitive deficits in mouse models of Aβ-amyloidosis (Laird et al. 2005, Luo et al. 2001, McConlogue et al. 2007, Ohno et al. 2004, Singer et al. 2005).”
From miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression (2016) · cites this paper as McConlogue et al. 2007
In in vivo model systems, similar magnitudes of Aβ reductions are sufficient to prevent or halt Aβ plaque accumulation.
“In in vivo model systems, similar magnitudes of Aβ reductions are sufficient to prevent or halt Aβ plaque accumulation (53, 54).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [53]
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“dramatic effects on amyloid deposition (11).”
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“However, modest reduction of BACE1 activity is sufficient for a significant reduction in brain A deposition in AD model mice (McConlogue et al., 2007; Chow et al., 2010).”
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BackgroundThe Neural Cell Adhesion Molecules L1 and CHL1 Are Cleaved by BACE1 Protease in Vivo*
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“Ab deposition is significantly reduced in the brains of old AD models when the mice have a 50% knockdown of cerebral BACE1 protein [26,86,87].”
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“Furthermore, BACE1 heterozygous knockout mice have no reported abnormal phenotypes so far and heterozygous knockout of BACE1 still can reduce Aβ deposition in AD mice [97,98].”
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“Based on ADmouse model studies, it is hypothesized that 50% BACE1 inhibition is necessary to delay or prevent amyloid deposition (17, 57).”
MethodSecretase inhibitors and modulators for Alzheimer’s disease treatment
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“The Aβ42 and Aβ40 monomers concentrations were determined using ELISA kit (human β amyloid [1-40] and [1-42] kits, Wako, Osaka, Japan).”
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“the course of disease progression [20]; however, the underlying”
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“Notably, recent data demonstrated that BACE1+/) deletion can reduce AD neuropathological changes such as Ab plaques and neuritic dystrophy in transgenic mice over-expressing mutated human APP(V717F) under the platelet-derived growth factor promoter (PDAPP) transgenic mice (McConlogue et al. 2007).”
InfluentialScott, J. D., Li, S. W., Brunskill, A., Chen, X., Cox, K., Cumming, J., Forman, M., Gilbert, E., Hodgson, R., Hyde, L., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00307 · Cited by 137 · see citing works
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“Absence of BACE-1 in BACE-1-knockout/ APP-transgenic mice reduced the A -load in comparison to APP-transgenic mice with endogenous BACE-1 activity [106–108].”
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“…finding dovetails with the observation in BACE1 heterozygous KO crossed with PDAPP transgenic mice, in which soluble A levels were lowered only by 12% at a young age, whereas A -accumulation was eventually reduced by 50–90% with synaptic amelioration in elderly animals (McConlogue et al., 2007).”
BackgroundThe β-secretase enzyme BACE1 as a therapeutic target for Alzheimer's disease
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“In a similar study, McConlogue and colleagues reported a signifi cantly reduced Aβ burden in the brains of 13-month-old and 18-month-old PDAPP;BACE1+/– mice [62].”
The case for low-level BACE1 inhibition for the prevention of Alzheimer disease
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Soluble Aβ Promotes Wild-Type Tau Pathology<i>In Vivo</i>
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“3E), consistent with previous studies (McConlogue et al., 2007), while APP expression remains unchanged (Fig.”
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“…demonstrated that the abilities of BACE1 +/− deletion to reduce Aβ levels or plaque load in brains of APP transgenic mice including the 5XFAD model become smaller and eventually disappear during the course of disease progression (Devi and Ohno, 2010b; Laird et al., 2005; McConlogue et al., 2007).”
Treatment Strategies Targeting Amyloid -ProteinPreprint
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“Delayed onset of AD pathology in APP BACE1þ/2 mice suggest that, as with GSIs, partial inhibition of BACE1 may be a solution toward mitigating the potential safety issues associated with inhibiting this protease (Laird et al. 2005; McConlogue et al. 2007).”
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“Interestingly, reduced levels of BACE1 in double PDAPP/BACE(–/–) transgenic mice are associated with reduced b-amyloid plaque formation (40), and oral administration of a selective BACE1 inhibitor decreases b-amyloid production in vivo (24).”
BackgroundIdentification and biology of β‐secretase
Kandalepas, P. C., & Vassar, R. J. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07512.x · Cited by 79 · see citing works
“In addition, age-associated cognitive deficits were prevented in BACE1;APP bigenic mice (Luo et al. 2001, 2003; Ohno et al. 2004, 2007; Laird et al. 2005; Nishitomi et al. 2006; McConlogue et al. 2007; Kobayashi et al. 2008).”
BackgroundNeumann, U., Rueeger, H., Machauer, R., Veenstra, S. J., Lueoend, R. M., Tintelnot-Blomley, M., Laue, G., Beltz, K., Vogg, B., Schmid, P., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0033-8 · Cited by 113 · see citing works
“A study in BACE -/+ PDAPP mice has shown a similar moderate effect of reduced BACE1 activity on neocortical Aβ in young mice (-12 %, [18]).”
BackgroundHe, F.-Q., Qiu, B., Zhang, X.-H., Li, T.-K., Xie, Q., Cui, D.-J., Huang, X.-L., & Gan, H. (2011) · Brain Research · doi:10.1016/j.brainres.2011.01.103 · Cited by 113 · see citing works
Jeppsson, F., Eketjäll, S., Janson, J., Karlström, S., Gustavsson, S., Olsson, L., Radesater, A.-C., Ploeger, B., Cebers, G., Kolmodin, K., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.409110 · Cited by 111 · see citing works
Cathepsin B Degrades Amyloid-β in Mice Expressing Wild-type Human Amyloid Precursor Protein*
Wang, C., Sun, B.-G., Zhou, Y.-G., Grubb, A., & Gan, L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.371641 · Cited by 109 · see citing works
“Indeed, ablation of BACE1 completely abolished processing of the -secretase site and A generation in PDAPPmice, which overexpress hAPPV717F with nomutations at the -secretase site (22), further supporting the notion that BACE1, not CatB, is the major -secretase of hAPP with or without FAD mutations.”
BackgroundThe Role and Therapeutic Targeting of α-, β- and γ-Secretase in Alzheimer's Disease
MacLeod, R., Hillert, E., Cameron, R. T., & Baillie, G. S. (2015) · Future Science OA · doi:10.4155/fso.15.9 · Cited by 131 · see citing works
A G-RICH ELEMENT FORMS A G-QUADRUPLEX AND REGULATES BACE1 mRNA ALTERNATIVE SPLICING
Fisette, J.-F., Montagna, D. R., Mihailescu, M., & Wolfe, M. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07680.x · Cited by 107 · see citing works
“Indeed, it was shown in APP transgenic mice, that even a partial reduction of BACE1 can effectively decrease production of Ab and synaptic deficits (Laird et al. 2005; Singer et al. 2005; McConlogue et al. 2007).”
BackgroundEketjäll, S., Janson, J., Kaspersson, K., Bogstedt, A., Jeppsson, F., Fälting, J. M., Haeberlein, S. B., Kugler, A. R., Alexander, R. C., & Cebers, G. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150834 · Cited by 132 · see citing works
“Mice that express mutant A PP [11] show progressive A deposition, and reducing BACE1 activity yields large decreases in amyloid plaque load [12].”
BackgroundThe unsolved relationship of brain aging and late-onset Alzheimer disease.
Kern, A., & Behl, C. (2009) · Biochimica et Biophysica Acta · doi:10.1016/j.bbagen.2009.07.016 · Cited by 103 · see citing works
miR‐186 is decreased in aged brain and suppresses <scp>BACE</scp>1 expression
Kim, J., Yoon, H., Chung, D., Brown, J. L., Belmonte, K. C., & Kim, J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13507 · Cited by 102 · see citing works
“…unequivocally demonstrated that inhibition of BACE1 by RNAi-mediated knock-down or genetic deletion ameliorates Ab-associated pathologies and cognitive deficits in mouse models of Ab-amyloidosis (Luo et al. 2001; Ohno et al. 2004; Laird et al. 2005; Singer et al. 2005; McCon- logue et al. 2007).”
BackgroundLeveraging preclinical models for the development of Alzheimer disease therapeutics
Scearce-Levie, K. A., Sanchez, P. E., & Lewcock, J. W. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0065-9 · Cited by 118 · see citing works
Hitt, B. D., Jaramillo, T. C., Chetkovich, D. M., & Vassar, R. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-31 · Cited by 99 · see citing works
“This is highlighted by the finding that Ab generation, amyloid pathology, electrophysiological dysfunction, and cognitive deficits characteristic of APP transgenic mice are all abrogated by genetic deletion of BACE1 [11-15].”
BackgroundRueeger, H., Lueoend, R., Rogel, O., Rondeau, J., Mobitz, H., Machauer, R., Jacobson, L., Staufenbiel, M., Desrayaud, S., & Neumann, U. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300069y · Cited by 98 · see citing works
The Basic Biology of BACE1: A Key Therapeutic Target for Alzheimer’s Disease
Cole, S. L., & Vassar, R. (2007) · Current Genomics · doi:10.2174/138920207783769512 · Cited by 97 · see citing works
“McConlogue and colleagues recently reported that, in contrast to the observations of Laird, a 50% decrease in BACE1 levels exerts little impact on A levels in young APP Tg mice, but led to a dramatic reduction in A levels and synaptic deficits in aged mice [67].”
ResultJacobsen, H., Ozmen, L., Caruso, A., Narquizian, R., Hilpert, H., Jacobsen, B., Terwel, D., An, T.-H., & Bohrmann, B. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1405-14.2014 · Cited by 93 · see citing works
“Lowering BACE1 activity reduces the de novo formation of A , thus preventing its subsequent aggregation into toxic aggregates (Cai et al., 2001; Vassar, 2001; Citron, 2002; McConlogue et al., 2007).”
BackgroundJiang, Y., Rigoglioso, A., Peterhoff, C., Pawlik, M., Sato, Y., Bleiwas, C., Stavrides, P. H., Smiley, J., Ginsberg, S. D., Mathews, P., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.11.013 · Cited by 92 · see citing works
“reducing APP-bCTF while minimally changing Ab levels, as previously reported (McConlogue et al., 2007; Nishitomi et al., 2006), to investigate its possible therapeutic effects.”
InfluentialGaldeano, C., Viayna, E., Sola, I., Formosa, X., Camps, P., Badía, A., Clos, M. V., Relat, J., Ratia, M., Bartolini, M., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm200840c · Cited by 91 · see citing works
Understanding BACE1: essential protease for amyloid-β production in Alzheimer’s disease
Stockley, J., & O'Neill, C. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8271-3 · Cited by 87 · see citing works
Jia, Q., Deng, Y., & Qing, H. (2014) · BioMed Research International · doi:10.1155/2014/837157 · Cited by 80 · see citing works
“AD pathology onset was postponed in the APP × BACE1+/−mice; however, it hinted at a partial inhibition that might mitigate the potential safety problems [32, 33].”
BackgroundReduced Sodium Channel Nav1.1 Levels in BACE1-null Mice*
Kim, D. Y., Gersbacher, M. T., Inquimbert, P., & Kovacs, D. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.134692 · Cited by 86 · see citing works
Small-molecule BACE1 inhibitors: a patent literature review (2006 – 2011)
Probst, G. D., & Xu, Y. (2012) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2012.681302 · Cited by 76 · see citing works
“A 50% reduction in BACE1 enzyme levels in heterozygous transgenic mice resulted in a dramatic reduction in Ab plaques, neuritic burden, and synaptic deficits in aged mice [20].”
BackgroundMarginal vitamin A deficiency facilitates Alzheimer’s pathogenesis
Zeng, J., Chen, L., Wang, Z., Chen, Q., Fan, Z., Jiang, H., Wu, Y.-L., Ren, L., Chen, J., Li, T.-Y., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1669-y · Cited by 83 · see citing works
“Consistently, inhibition of BACE1 expression reduces Aβ generation and neuritic plaque formation, and rescues memory deficits in the AD model mice [37, 40, 43].”
BackgroundBACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology
Peters, F., Salihoglu, H., Rodrigues, E. F., Herzog, É., Blume, T., Filser, S., Dorostkar, M. M., Shimshek, D. R., Brose, N., Neumann, U., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-017-1804-9 · Cited by 86 · see citing works
“In addition, slight reduction of Aβ levels by 12% in BACE1+/− mice reduces total Aβ deposition by 50% in aged mice [62].”
Identification and biology of α‐secretase
Vingtdeux, V., & Marambaud, P. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07477.x · Cited by 81 · see citing works
Agostinho, P., Pliássova, A., Oliveira, C., & Cunha, R. (2015) · Journal of Alzheimer's Disease · doi:10.3233/jad-142730 · Cited by 78 · see citing works
“In contrast, the partial reduction of BACE1 activity was shown to ameliorate AD-like pathology, making BACE1 an excellent target for therapeutic intervention in AD [124, 127].”
BackgroundZhang, X., Li, L.-X., Zhang, X.-J., Xie, W.-J., Li, L., Yang, D.-H., Heng, X., Du, Y., Doody, R., & Le, W. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.06.012 · Cited by 78 · see citing works
“In order to detect the protein levels in the cortex, we used an anti-SYN antibody for immunofluorescent staining (McConlogue et al., 2007) and Western blot (Fig.”
MethodKindy, M., Yu, J., Zhu, H., El-Amouri, S. S., Hook, V., & Hook, G. R. (2012) · Journal of Alzheimer's Disease · doi:10.3233/jad-2012-111604 · Cited by 78
“brain A and amyloid plaque are reduced [14].”
Cebers, G., Alexander, R., Haeberlein, S. B., Han, D., Goldwater, R., Ereshefsky, L., Olsson, T., Ye, N., Rosen, L. B., Russell, M., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160701 · Cited by 92 · see citing works
“This hypothesis is supported by studies in transgenic mouse models of Alzheimer’s disease [9, 16–19] and most compellingly by human genetic associations.”
Yuksel, M., & Tacal, Ö. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172415 · Cited by 94 · see citing works
Lee, H. J., Ryu, J. M., Jung, Y., Lee, S.-J., Kim, J. Y., Lee, S.-H., Hwang, I., Seong, J., & Han, H. (2016) · Scientific Reports · doi:10.1038/srep36746 · Cited by 75 · see citing works
Khodadadi, D., Gharakhanlou, R., Naghdi, N., Salimi, M., Azimi, M., Shahed, A., & Heysieattalab, S. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2571-2 · Cited by 71 · see citing works
“In fact, even minimal decrease of soluble Aβ dramatically affects plaque formation at later ages [65].”
BackgroundHook, G., Yu, J., Toneff, T., Kindy, M. S., & HOOK, V. Y. H. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-131370 · Cited by 82 · see citing works
“Others have reported that deleting the BACE1 gene caused a decrease in flAβ in PDGF-AβPP [88] or AβPP51/16 mice [89], which express AβPP-751/770 and AβPP-751, respectively, containing the wt β-secretase site sequence, whereas we show here and previously that the BACE1 gene deletion in AβPPLon mice expressing AβPP-695…”
Poon, C., Shah, K., Lin, C., Tse, R., Kim, K. K., Mooney, S. J., Aubert, I., Stefanovic, B., & Hynynen, K. (2018) · Scientific Reports · doi:10.1038/s41598-018-32250-3 · Cited by 80 · see citing works
Uno, Y., Piao, W., Miyata, K., Nishina, K., Mizusawa, H., & Yokota, T. (2011) · Human Gene Therapy · doi:10.1089/hum.2010.083 · Cited by 71 · see citing works
“Single allele ablation caused only a 12% decrease in Ab level, but nonetheless resulted in four- to fivefold fewer Ab plaques (McConlogue et al., 2007).”
BackgroundHOOK, V. Y. H., Funkelstein, L., Wegrzyn, J., Bark, S. J., Kindy, M. S., & Hook, G. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.08.015 · Cited by 70 · see citing works
Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease
Yan, R., Fan, Q., Zhou, J., & Vassar, R. J. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.025 · Cited by 71 · see citing works
“In BACE1-null mice, Aβ generation is almost abolished, and significant reductions in Aβ are seen in BACE1 heterozygous mice (McConlogue et al., 2007).”
Devi, L., & Ohno, M. (2009) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2009.07031.x · Cited by 67 · see citing works
“Furthermore, partial reduction of BACE1 due to its heterozygous knockout (BACE1+/−) suffices to lower cerebral Aβ levels and rescue hippocampal memory deficits in APP mice (McConlogue et al., 2007; Ohno and Kimura, 2008).”
BackgroundDepletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1
Walker, K. R., Kang, E. L., Whalen, M. J., Shen, Y., & Tesco, G. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.5491-11.2012 · Cited by 66 · see citing works
“BACE1 haploinsufficiency results in a minimal reduction of A in BACE1( / )/ APP transgenic mice at 3 months of age and a 90% and 50% reduction of A levels at 13 and 18 months of age, respectively (McConlogue et al., 2007).”
BackgroundInhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes
Du, Y., Zhao, Y., Li, C.-B., Zheng, Q.-Y., Tian, J., Li, Z.-Y., Huang, T. Y., Zhang, W., & Xu, H.-X. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20171193 · Cited by 66 · see citing works
“…inhibitors decreases APP β cleavage and Aβ production in APP-transgenic mice, suggesting that even a partial reduction in BACE1 can have dramatically beneficial effects on AD pathology (Kao et al., 2004; Hussain et al., 2007; McConlogue et al., 2007; Neumann et al., 2015; Pigoni et al., 2016).”
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
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 282
- Issue
- 36
- Pages
- 26326-26334
- ISSN
- 0021-9258 (ISSN-L)
- 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
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › 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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