Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein

Citron, Martin; Eckman, Christopher B.; Diehl, Thekla S.; Corcoran, Chris; Ostaszewski, Beth L.; Xia, Weiming; Levesque, Georges; St. George Hyslop, Peter; Younkin, Steven G.; Selkoe, Dennis J.

doi:10.1006/nbdi.1998.0183

Cited by 103Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein

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Citron, Martin, Eckman, Christopher B., Diehl, Thekla S., Corcoran, Chris, Ostaszewski, Beth L., Xia, Weiming, Levesque, Georges, St. George Hyslop, Peter +2 more·1998·Neurobiology of Disease

DOI 10.1006/nbdi.1998.0183

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Abstract

Humans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid beta-protein (A beta 42) at an early age and develop severe Alzheimer's disease. A beta 42 is selectively elevated in the conditioned media of cells expressing mutant but not wild-type PS1, indicating that presenilin mutations alter APP processing. Here we analyze the effects of various PS1 mutant constructs on the cellular production of A beta 42. A construct expressing only the PS1 N-terminal endoproteolytic fragment with the mutation Y115H causes no significant increase in A beta 42, whereas a full-length PS1 construct with the same mutation does. This result suggests that the pathogenic effect of mutant presenilins is produced by the full-length molecule even though only a minor proportion of total PS1 occurs as holoprotein in tissues and cell lines. We demonstrate that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule. Therefore, two mutations alter gamma-secretase processing of APP more than one and the PS1 mutations described to date do not cause the maximum possible PS1-mediated rise in A beta 42. When a PS1 mutation was expressed in cells carrying the APPV717I mutation, A beta 42 rose dramatically to become the predominant secreted A beta species, an observation of interest for transgenic modeling of AD. Our results are consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by gamma-secretases.

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Intermolecular combination of Aβ42-elevating mutations in APP and PS1 additively increased Aβ42 production.
“Moreover, the intermolecular combination of A 𝛃 42 -elevating mutations in APP and PS1 also additively increased A 𝛃 42 production (Citron et al., 1998).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Citron et al., 1998
The two PS1 FAD mutations M146L and L286V, when introduced together into PS1, doubled Aβ42 production compared with the individual mutations.
“In particular, the intramolecular combination of I716V and V717I mutations within APP doubled A 𝛃 42 production compared with the individual mutations (Eckman et al., 1997), as did the two PS1 FAD mutations M146L and L286V when introduced together into PS1 (Citron et al., 1998).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Citron et al., 1998
The 5XFAD mouse is one of a few known mouse models that exhibits significant neuron loss in addition to displaying other AD hallmarks such as amyloid plaques.
“The 5XFAD mouse, along with the APPSLPS1KI, is one of a few known mouse models that exhibits significant neuron loss in addition to displaying other AD hallmarks such as amyloid plaques [10,11,16].”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [11]
Frank neuron loss has been observed in 5XFAD and APPSLPS1KI transgenic mouse models that also exhibit intraneuronal Aβ42 prior to plaque formation.
“Frank neuron loss has been observed in two aggressive amyloid plaque transgenic mouse models that also exhibit accumulation of intraneuronal Aβ42 prior to plaque formation: the 5XFAD and APPSLPS1K1 lines [10,11].”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [11]

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Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice
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Authors: Citron, M., Eckman, C. B., Diehl, T. S., Corcoran, C., Ostaszewski, B. L., Xia, W., Levesque, G., St. George Hyslop, P., Younkin, S. G., & Selkoe, D. J.
Affiliations: Amgen (United States) (US)
Mayo Clinic (US)
Harvard University (US)
ORCID: Citron, Martin
Corcoran, Chris
Xia, Weiming
Selkoe, Dennis J.
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 1998-08
Volume: 5
Issue: 2
Pages: 107-116
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1006/nbdi.1998.0183
OpenAlex: W2012968591
Cited by: 101
References: 28
Citations by year: 2026: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 3 · 2012: 2
FWCI: 5.67
Type: journal article
Language: en
Open access: green
doaj.org
Licence: cc-by-sa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Disease (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health
National Institute on Aging (AG 12749, AG-06173, R01AG012749)
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, APP mutations, amyloid-beta 42, gamma-secretase, APP processing, Alzheimer's disease, conditioned medium, transgenic mouse model
MeSH terms: Alzheimer Disease, Cell Line, Gene Expression Regulation, Humans, Leucine, Membrane Proteins, Methionine, Peptide Fragments, Valine, Amyloid beta-Peptides, Mutagenesis, Site-Directed, Amyloid beta-Protein Precursor, Age of Onset, Amino Acid Substitution, Presenilin-1

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Additive Effects of PS1 and APP Mutations on Secretion of the 42-Residue Amyloid β-Protein

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