Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level

Sadleir, Katherine R; Eimer, William A; Cole, Sarah L; Vassar, Robert

doi:10.1186/1750-1326-10-1

Cited by 213Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level

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Sadleir, Katherine R, Eimer, William A, Cole, Sarah L, Vassar, Robert·2015·Molecular Neurodegeneration

DOI 10.1186/1750-1326-10-1PMC PMC4297413

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Abstract

BACKGROUND: The β-secretase, BACE1, cleaves APP to initiate generation of the β-amyloid peptide, Aβ, that comprises amyloid plaques in Alzheimer's disease (AD). Reducing BACE1 activity is an attractive therapeutic approach to AD, but complete inhibition of BACE1 could have mechanism-based side-effects as BACE1-/- mice show deficits in axon guidance, myelination, memory, and other neurological processes. Since BACE1+/- mice appear normal there is interest in determining whether 50% reduction in BACE1 is potentially effective in preventing or treating AD. APP transgenic mice heterozygous for BACE1 have decreased Aβ but the extent of reduction varies greatly from study to study. Here we assess the effects of 50% BACE1 reduction on the widely used 5XFAD mouse model of AD. RESULTS: 50% BACE1 reduction reduces Aβ42, plaques, and BACE1-cleaved APP fragments in female, but not in male, 5XFAD/BACE1+/- mice. 5XFAD/BACE1+/+ females have higher levels of Aβ42 and steady-state transgenic APP than males, likely caused by an estrogen response element in the transgene Thy-1 promoter. We hypothesize that higher transgenic APP level in female 5XFAD mice causes BACE1 to no longer be in excess over APP so that 50% BACE1 reduction has a significant Aβ42 lowering effect. In contrast, the lower APP level in 5XFAD males allows BACE1 to be in excess over APP even at 50% BACE1 reduction, preventing lowering of Aβ42 in 5XFAD/BACE1+/- males. We also developed and validated a dot blot assay with an Aβ42-selective antibody as an accurate and cost-effective alternative to ELISA for measuring cerebral Aβ42 levels. CONCLUSIONS: 50% BACE1 reduction lowers Aβ42 in female 5XFAD mice only, potentially because BACE1 is not in excess over APP in 5XFAD females with higher transgene expression, while BACE1 is in excess over APP in 5XFAD males with lower transgene expression. Our results suggest that greater than 50% BACE1 inhibition might be necessary to significantly lower Aβ, given that BACE1 is likely to be in excess over APP in the human brain. Additionally, in experiments using the 5XFAD mouse model, or other Thy-1 promoter transgenic mice, equal numbers of male and female mice should be used, in order to avoid artifactual gender-related differences.

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In the 5XFAD model, Aβ accumulation in females was almost double that of males.
“Consistent with the reported phenotypes of the 5XFAD model17, we found that Aβ accumulation in females was almost double that of males.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [17]
The Results section reports higher cerebral Aβ42 levels and more plaques in female than male 5XFAD mice, particularly for the BACE1+/+ genotype. It does not give an almost-twofold female-to-male Aβ comparison in the retrieved passages; the approximately 50% lower values reported for males concern the APP cleavage products sAPPβ and C99, not Aβ42. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In the 5XFAD model, Aβ accumulation in females is almost double that of males.
“Consistent with the reported phenotypes of the 5XFAD model17, we found that Aβ accumulation in females was almost double that of males.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [17]
The Results section reports higher cerebral Aβ42 levels and more plaques in female than male 5XFAD mice, at least for the BACE1+/+ genotype. It does not quantify female Aβ accumulation as almost double male accumulation; the approximately 50% male levels reported elsewhere in Results concern APP cleavage products, not Aβ42. Page numbers were not provided in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
The 5XFAD mouse model has a significant sex difference in Aβ levels and amyloid deposition.
“Because 5XFAD mouse model has a significant sex difference in Aβ levels and amyloid deposition17, we performed all statistical analyses for males and females separately.”
From Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis (2024) · cites this paper as [17]
5XFAD mice are known to have a sex-dependent difference in the extent of amyloid accumulation.
“Because 5XFAD mice are known to have a sex-dependent difference in the extent of amyloid accumulation (25), we designed our study to consider sex difference, analyzing the results separately between male and female mice.”
From Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis (2021) · cites this paper as [25]
Female 5XFAD mice have increased BACE1 activity, leading to increased amyloid plaque burden compared to male 5XFAD mice.
“Females also appear to have increased BACE1 activity, a β-secretase processing enzyme which cleaves pAPP and produces pathogenic Aβ fragments [40,41], ultimately leading to increased amyloid plaque burden compared to male 5XFAD mice [41,42].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [40]

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“Females also appear to have increased BACE1 activity, a β-secretase processing enzyme which cleaves pAPP and produces pathogenic Aβ fragments [40,41], ultimately leading to increased amyloid plaque burden compared to male 5XFAD mice [41,42].”
Background
RETRACTED ARTICLE: Solid lipid curcumin particles provide greater anti-amyloid, anti-inflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer’s disease
Maiti, P., Paladugu, L., & Dunbar, G. L. (2018) · BMC Neuroscience · doi:10.1186/s12868-018-0406-3 · Cited by 87 · see citing works
Retracted
Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α pathway in Alzheimer’s disease
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The bidirectional lung brain-axis of amyloid-β pathology: ozone dysregulates the peri-plaque microenvironment
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ApoE-2 Brain-Targeted Gene Therapy Through Transferrin and Penetratin Tagged Liposomal Nanoparticles
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Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice
Chen, L., Dar, N. J., Na, R., McLane, K. D., Yoo, K., Han, X., & Ran, Q. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.01.002 · Cited by 80 · see citing works
The TGF-β Family inCaenorhabditis elegansPreprint
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Water exchange rate across the blood‐brain barrier is associated with CSF amyloid‐β 42 in healthy older adults
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Endothelial Control of Cerebral Blood Flow
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A comparative study of dietary curcumin, nanocurcumin, and other classical amyloid-binding dyes for labeling and imaging of amyloid plaques in brain tissue of 5×-familial Alzheimer’s disease mice
Maiti, P., Hall, T. C., Paladugu, L., Kolli, N., Learman, C. R., Rossignol, J., & Dunbar, G. L. (2016) · Histochemistry and Cell Biology · doi:10.1007/s00418-016-1464-1 · Cited by 75 · see citing works
Melatonin as a mitochondrial protector in neurodegenerative diseases
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Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1
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Loss of Ataxin-1 Potentiates Alzheimer's Pathogenesis by Elevating Cerebral BACE1 Transcription
Suh, J., Romano, D. M., Nitschke, L., Herrick, S. P., DiMarzio, B. A., Dzhala, V., Bae, J., Oram, M. K., Zheng, Y., Hooli, B., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.043 · Cited by 68 · see citing works
Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression
Liebsch, F., Kulic, L., Teunissen, C. E., Shobo, A., Ulku, I., Engelschalt, V., Hancock, M. A., van der Flier, W. M., Kunach, P., Rosa‐Neto, P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10152-w · Cited by 64 · see citing works
Rare TREM2 variants associated with Alzheimer’s disease display reduced cell surface expression
Sirkis, D. W., Bonham, L. W., Aparicio, R. E., Geier, E. G., Ramos, E. M., Wang, Q., Karydas, A., Miller, Z. A., Miller, B. L., Coppola, G., et al. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0367-7 · Cited by 61 · see citing works
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CD11a expression distinguishes infiltrating myeloid cells from plaque‐associated microglia in Alzheimer's disease
Shukla, A., McIntyre, L. L., Marsh, S. E., Schneider, C. A., Hoover, E. M., Walsh, C. M., Lodoen, M. B., Blurton-Jones, M. M., & Inlay, M. A. (2018) · Glia · doi:10.1002/glia.23575 · Cited by 59 · see citing works
Caffeoylquinic Acids in Centella asiatica Reverse Cognitive Deficits in Male 5XFAD Alzheimer’s Disease Model Mice
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Deletion of Abi3 gene locus exacerbates neuropathological features of Alzheimer’s disease in a mouse model of Aβ amyloidosis
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Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease
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Piperine in combination with quercetin halt 6-OHDA induced neurodegeneration in experimental rats: Biochemical and neurochemical evidences
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ER stress is not elevated in the 5XFAD mouse model of Alzheimer's disease
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Reduction of the expression of the late-onset Alzheimer’s disease (AD) risk-factor BIN1 does not affect amyloid pathology in an AD mouse model
Andrew, R. J., De Rossi, P., Nguyen, P., Kowalski, H. R., Recupero, A. J., Guerbette, T., Krause, S. V., Rice, R. C., Laury-Kleintop, L., Wagner, S. L., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006379 · Cited by 55 · see citing works
Pedunculopontine Nucleus Degeneration Contributes to Both Motor and Non-Motor Symptoms of Parkinson’s Disease
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Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer’s disease
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Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease
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Sex Differences between Neuronal Loss and the Early Onset of Amyloid Deposits and Behavioral Consequences in 5xFAD Transgenic Mouse as a Model for Alzheimer’s Disease
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Clusterin Is Required for β-Amyloid Toxicity in Human iPSC-Derived Neurons
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Expression of BC1 Impairs Spatial Learning and Memory in Alzheimer’s Disease Via APP Translation
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Aquaporins in Nervous System
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Consequences of Pharmacological BACE Inhibition on Synaptic Structure and Function
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Cerebrovascular phenotypes in mouse models of Alzheimer’s disease
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The role of mTORC1 activation in seizure-induced exacerbation of Alzheimer's disease
Gourmaud, S., Stewart, D. A., Irwin, D. J., Roberts, N., Barbour, A. J., Eberwine, G., O’Brien, W. T., Vassar, R. J., Talos, D. M., & Jensen, F. E. (2021) · Brain · doi:10.1093/brain/awab268 · Cited by 48 · see citing works
Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer’s disease
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Stress Granules and ALS: A Case of Causation or Correlation?
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Coenzyme Q10 Prevents Mitochondrial Dysfunction and Facilitates Pharmacological Activity of Atorvastatin in 6-OHDA Induced Dopaminergic Toxicity in Rats
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Tau deletion reduces plaque‐associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease
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Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice
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Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein
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Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease
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Neuroprotective Effects of Simvastatin and Cilostazol in l-Methionine-Induced Vascular Dementia in Rats
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Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene
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Every-other-day feeding exacerbates inflammation and neuronal deficits in 5XFAD mouse model of Alzheimer's disease
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Cognitive decline in Tg2576 mice shows sex-specific differences and correlates with cerebral amyloid-beta
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Targeting alpha-synuclein via the immune system in Parkinson's disease: Current vaccine therapies
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Clinical and Dopamine Transporter Imaging Trajectories in a Cohort of Parkinson's Disease Patients with GBA Mutations
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ANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells
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Alzheimer’s disease-associated β-amyloid does not protect against herpes simplex virus 1 infection in the mouse brain
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Search Strategy Analysis of 5xFAD Alzheimer Mice in the Morris Water Maze Reveals Sex- and Age-Specific Spatial Navigation Deficits
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BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice
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Intact olfactory memory in the 5xFAD mouse model of Alzheimer’s disease from 3 to 15 months of age
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Zebrafish an experimental model of Huntington’s disease: molecular aspects, therapeutic targets and current challenges
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Current knowledge and challenges associated with targeted delivery of neurotrophic factors into the central nervous system: focus on available approaches
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Post-Translational Modifications of BACE1 in Alzheimer's Disease
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Characterization of Apathy-Like Behaviors in the 5xFAD Mouse Model of Alzheimer's Disease
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Authors: Sadleir, K. R., Eimer, W. A., Cole, S. L., & Vassar, R.
Affiliations: Northwestern University (US)
Corresponding author: Vassar, Robert
ORCID: Sadleir, Katherine R
Eimer, William A
Vassar, Robert
Venue: Molecular Neurodegeneration
Publisher: Springer Science and Business Media LLC
Published: 2015-01-07
Volume: 10
Issue: 1
Pages: 1-1
ISSN: 1750-1326 (ISSN-L)
DOI: 10.1186/1750-1326-10-1
PMC: PMC4297413
OpenAlex: W2137860879
Cited by: 213
References: 45
Citations by year: 2026: 15 · 2025: 18 · 2024: 14 · 2023: 12 · 2022: 12 · 2021: 42 · 2020: 18 · 2019: 22 · 2018: 18 · 2017: 22 · 2016: 18 · 2015: 2
FWCI: 14.74
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Molecular Neurodegeneration (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Northwestern University (CA060553, NCI CA060553)
National Institutes of Health (CA-060553, AG022560, NCI CA060553)
National Institute on Aging (RF1AG022560, R01AG030142, R01AG022560, 5T32AG00026, F32AG033445)
National Cancer Institute (CA 060553, NCI CA060553, P30CA060553)
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, amyloid-beta, amyloid-beta 42, 5xFAD mice, Alzheimer's disease, sex differences, estrogen response element, dot blot, amyloid plaques, BACE1 inhibition, axon guidance, myelination, memory impairment
MeSH terms: Alzheimer Disease, Animals, Brain, Disease Models, Animal, Heterozygote, Humans, Memory, Mice, Transgenic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Knockout, Amyloid Precursor Protein Secretases, Plaque, Amyloid

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Aβ reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level

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