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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
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 [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]
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“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]
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“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]
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“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
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“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
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“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]
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“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]
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“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]
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“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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Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
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“4-mo-old male APPswe/PS1 E9 mice (Jankowsky et al., 2004) were intraperitoneally injected weekly for 14 wk with PBS or anti-apoE antibody (HJ6.”
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Metadata
- 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
- 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
- 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
- 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
- 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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