Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase

Jankowsky, Joanna L.; Fadale, Daniel J.; Anderson, Jeffrey; Xu, Guilian M.; Gonzales, Victoria; Jenkins, Nancy A.; Copeland, Neal G.; Lee, Michael K.; Younkin, Linda H.; Wagner, Steven L.; Younkin, Steven G.; Borchelt, David R.

doi:10.1093/hmg/ddh019

Cited by 1,575Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase

Jankowsky, Joanna L., Fadale, Daniel J., Anderson, Jeffrey, Xu, Guilian M., Gonzales, Victoria, Jenkins, Nancy A., Copeland, Neal G., Lee, Michael K. +4 more·2004·Human Molecular Genetics

DOI 10.1093/hmg/ddh019

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Abstract

Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and gamma-secretase to release amyloid peptides (Abeta40 and 42) that aggregate to form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus of Abeta40/42 is generated by gamma-secretase, whose activity is dependent upon presenilin (PS 1 or 2). Missense mutations in PS1 (and PS2) occur in patients with early-onset familial AD (FAD), and previous studies in transgenic mice and cultured cell models demonstrated that FAD-PS1 variants shift the ratio of Abeta40 : 42 to favor Abeta42. One hypothesis to explain this outcome is that mutant PS alters the specificity of gamma-secretase to favor production of Abeta42 at the expense of Abeta40. To test this hypothesis in vivo, we studied Abeta40 and 42 levels in a series of transgenic mice that co-express the Swedish mutation of APP (APPswe) with two FAD-PS1 variants that differentially accelerate amyloid pathology in the brain. We demonstrate a direct correlation between the concentration of Abeta42 and the rate of amyloid deposition. We further show that the shift in Abeta42 : 40 ratios associated with the expression of FAD-PS1 variants is due to a specific elevation in the steady-state levels of Abeta42, while maintaining a constant level of Abeta40. These data suggest that PS1 variants do not simply alter the preferred cleavage site for gamma-secretase, but rather that they have more complex effects on the regulation of gamma-secretase and its access to substrates.

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Dozens of mouse lines overexpressing several combinations of APP and PSEN1 mutations have been created to accelerate the onset of Aβ pathologies in brains.
“dozens of mouse lines overexpressing several combinations of APP and PSEN1 mutations have been created to accelerate the onset of Aβ pathologies in brains [28–30].”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [28]
The Introduction (p. 2) and Figure 2 (p. 4) describe APP-mutant mice co-expressing different PS1 mutations and show that co-expression accelerates brain amyloid deposition. The Generation of transgenic mice section (p. 8) identifies several lines, but this paper does not establish that dozens of such lines have been created. (LLM, conf=0.86)
Experimental — accuracy not yet measured
WAVE1 knockout dramatically reduces Aβ levels and restores memory deficits in APP/PS1 transgenic mice expressing familial mutations in APP (APPswe) and presenilin 1 (PSEN1 ΔE9).
“WAVE1 KO dramatically reduces Aβ levels and restores memory deficits in APP/PS1 transgenic mice expressing familial mutations in APP (APPswe) and presenilin 1 (PSEN1 ΔE9)146, suggesting a protective role for reduced WAVE1 expression in AD143.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [146]
Figure 2 (p. 4) identifies APPswe/PS1-ΔE9 transgenic mice, supporting the description of the mouse model. The Discussion (p. 4) reports that mutant PS1 increases Aβ42, but the paper does not report WAVE1 knockout, a WAVE1-related reduction in Aβ, or restoration of memory deficits. (LLM, conf=0.89)
Experimental — accuracy not yet measured
C1q was similarly increased in hippocampus of APP/PS1 mice.
“C1q was also similarly increased in hippocampus of another model of AD, the APP/PS1 mice (15) (Fig. S2C).”
From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [15]
APP/PS1 transgenic mice overexpress a chimeric mouse/human APP695 swedish gene and human PSEN1 with an exon 9 deletion.
“APP/PS1 transgenic mice overexpress a chimeric mouse/human APP695 swedish gene and human PSEN1 with an exon 9 deletion (Jankowsky et al., 2004).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Jankowsky et al., 2004
9-mo-old APPswe/PS1ΔE9 mice have preexisting fibrillar plaques.
“Because we used 9-mo-old APPswe/PS1ΔE9 mice with preexisting fibrillar plaques (Jankowsky et al., 2004), we calculated HJ6.3-induced microglial activation after normalizing with fibrillar plaque load.”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as Jankowsky et al., 2004

The consequences of GDE2 ablation on the timing and amount of Aβ40 and Aβ42 production in APP/PS1 mice are likely influenced by the dynamics of APP processing effected by the AD-associated mutations in human APP and PSEN1 expressed by APP/PS1 animals.
“In this context, the consequences of GDE2 ablation on the timing and the amount of Aβ40 and Aβ42 peptide production is likely influenced by the dynamics of APP processing effected by the AD-associated mutations in human APP and PSEN1 (γ-secretase) proteins expressed by APP/PS1 animals (32).”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [32]
Unlike 3xTg, APP transgene in APP-PS1 is controlled by PrP promoter, exclusively expressed in neurons but not T-cells of APP-PS1 mice.
“Unlike the 3xTg mice, the APP transgene in the APP-PS1 mouse model is controlled by the prion protein (PrP) promoter (41), which is exclusively expressed in the neurons but not in T-cells of the APP-PS1 mice (Figure 1J, right panel).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [41]
One of the metabolic signatures of ceramide-dependent mitophagy in aging neurons is the depletion of fumarate.
“One of the metabolic signatures of ceramide-dependent mitophagy in aging neurons is the depletion of fumarate (41).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [41]
The Introduction (p. 2) and Discussion (p. 4) address presenilin mutations, amyloid-β levels, and amyloid deposition. Searches for fumarate, ceramide, and mitophagy found no passage addressing fumarate depletion during ceramide-dependent mitophagy in aging neurons. (LLM, conf=0.77)
Experimental — accuracy not yet measured
Hippocampal Fndc5 expression is significantly reduced at six months of age in APP/PS1 mice compared with WT littermates.
“Hippocampal Fndc5 gene expression is significantly reduced at six months of age in the well-established transgenic AD mouse model APP/PS1 (APPswe,PSEN1dE9)51,52 compared to WT littermates (Fig. 6a).”
From Exercise hormone irisin is a critical regulator of cognitive function (2021) · cites this paper as [51]

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Purification, ultrastructure, and chemical analysis of Alzheimer disease amyloid plaque core protein.
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Drosophila Nicastrin Is Essential for the Intramembranous Cleavage of Notch
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Multiple Effects of Aspartate Mutant Presenilin 1 on the Processing and Trafficking of Amyloid Precursor Protein
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FAD Mutations in Presenilin-1 or Amyloid Precursor Protein Decrease the Efficacy of a γ-Secretase Inhibitor: Evidence for Direct Involvement of PS1 in the γ-Secretase Cleavage Complex
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Complement and microglia mediate early synapse loss in Alzheimer mouse models
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“Given that AD has a complex pathology and that therapies that effectively halt the disease progression are still lacking, recent studies have focused on environmental components and diet-based possible prevention strategies by using transgenic animal models (161, 162).”
Background
Pathological roles of MAPK signaling pathways in human diseases
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“This process is observed at the age of 8 months and appears to precede or parallel the increase in A levels observed in PS1-APP mice at that age (Jankowsky et al., 2001, 2004).”
Background
Gamma frequency entrainment attenuates amyloid load and modifies microglia
Iaccarino, H. F., Singer, A. C., Martorell, A. J., Rudenko, A., Gao, F., Gillingham, T. Z., Mathys, H., Seo, J., Kritskiy, O., Abdurrob, F., et al. (2016) · Nature · doi:10.1038/nature20587 · Cited by 1,328 · see citing works
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Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
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Human Health Risk Assessment for Aluminium, Aluminium Oxide, and Aluminium Hydroxide
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Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
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Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
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Neuronal activity regulates the regional vulnerability to amyloid-β deposition
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Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup
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The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans
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Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus
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Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease
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Identification of amyloid plaques in retinas from Alzheimer's patients and noninvasive in vivo optical imaging of retinal plaques in a mouse model
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Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease
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Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
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Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
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Molecular basis of astrocyte diversity and morphology across the CNS in health and disease
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Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease
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Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models
Cruz Hernández, J. C., Bracko, O., Kersbergen, C. J., Muse, V., Haft-Javaherian, M., Berg, M., Park, L., Vinarcsik, L. K., Ivasyk, I., Rivera, D. A., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0329-4 · Cited by 508 · see citing works
ApoE4 Accelerates Early Seeding of Amyloid Pathology
Liu, C.-C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.-W., & Bu, G. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.013 · Cited by 451 · see citing works
Reduced IGF-1 signaling delays age-associated proteotoxicity in mice
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NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency
Hou, Y., Lautrup, S., Cordonnier, S., Wang, Y., Croteau, D. L., Zavala, E., Zhang, Y., Moritoh, K., O’Connell, J. F., Baptiste, B. A., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1718819115 · Cited by 472 · see citing works
Microglia use TAM receptors to detect and engulf amyloid β plaques
Huang, Y., Happonen, K. E., Burrola, P. G., O’Connor, C., Hah, N., Huang, L., Nimmerjahn, A., & Lemke, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00913-5 · Cited by 483 · see citing works
Elusive roles for reactive astrocytes in neurodegenerative diseases
Ben Haim, L., Carrillo-de Sauvage, M.-A., CeyzÃ©riat, K., & Escartin, C. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00278 · Cited by 453 · see citing works
Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo
Busche, M. A., Wegmann, S., Dujardin, S., Commins, C., Schiantarelli, J., Klickstein, N., Kamath, T. V., Carlson, G. A., Nelken, I., & Hyman, B. T. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0289-8 · Cited by 413 · see citing works
Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models
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Sustained hippocampal IL-1β overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology
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Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer’s Model
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Resveratrol Mitigates Lipopolysaccharide- and Aβ-Mediated Microglial Inflammation by Inhibiting the TLR4/NF-Κb/STAT Signaling cascade
Capiralla, H., Vingtdeux, V., Zhao, H., Sankowski, R., Al‐Abed, Y., Davies, P., & Marambaud, P. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07594.x · Cited by 426 · see citing works
PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease
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Memory Impairment in Transgenic Alzheimer Mice Requires Cellular Prion Protein
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Exercise hormone irisin is a critical regulator of cognitive function
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Aβ is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis
Herzig, M. C., Winkler, D. T., Burgermeister, P., Pfeifer, M., Kohler, E., Schmidt, S. D., Danner, S., Abramowski, D., Stürchler-Pierrat, C., Bürki, K., et al. (2004) · Nature Neuroscience · doi:10.1038/nn1302 · Cited by 391 · see citing works
Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology
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IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline
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Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease
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“Cg-Tg(Gfap-cre)73.12Mvs/J], also obtained from Jackson Laboratories, to generate mice that lacked PPAR expression in astrocytes and cortical neurons.”
Method
Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease
Chen, J.-F., Liu, K., Hu, B., Li, R.-R., Xin, W., Chen, H., Wang, F., Chen, L., Li, R.-X., Ren, S.-Y., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.012 · Cited by 346 · see citing works
ApoE facilitates the microglial response to amyloid plaque pathology
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Inhibition of Stat3‐mediated astrogliosis ameliorates pathology in an Alzheimer's disease model
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Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease
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The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer’s and Huntington’s diseases
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Method
Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis
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Method
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Authors: Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., Younkin, S. G., & Borchelt, D. R.
Affiliations: California Institute of Technology (US)
Mayo Clinic (US)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Johns Hopkins University (US)
National Institutes of Health (US)
Corresponding author: Jankowsky, Joanna L.
ORCID: Jankowsky, Joanna L.
Xu, Guilian M.
Jenkins, Nancy A.
Lee, Michael K.
Wagner, Steven L.
Younkin, Steven G.
Borchelt, David R.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2003-11-25
Volume: 13
Issue: 2
Pages: 159-170
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddh019
OpenAlex: W2142943752
Cited by: 1,575
References: 80
Citations by year: 2026: 63 · 2025: 99 · 2024: 104 · 2023: 83 · 2022: 115 · 2021: 111 · 2020: 132 · 2019: 96 · 2018: 88 · 2017: 81 · 2016: 91 · 2015: 90 · 2014: 68 · 2013: 69 · 2012: 66
FWCI: 8.84
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders: National Institute on Aging (1 P01 AG-98-003, 1 P50 AG-14-248)
National Institute of Neurological Disorders and Stroke (1 T32 NS07435, T32NS007435)
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: presenilin 1, presenilin 2, gamma-secretase, amyloid-beta 42, Aβ40, Alzheimer's disease, familial Alzheimer's disease, APPswe, transgenic mice, amyloid deposition
MeSH terms: Alzheimer Disease, Animals, Brain, Cells, Cultured, Humans, Membrane Proteins, Mice, Transgenic, Peptide Fragments, Endopeptidases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Age of Onset, Mutation, Missense, Mice, Presenilin-1, Amyloid Precursor Protein Secretases

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Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase

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