A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

Dolev, Iftach; Michaelson, Daniel M.

doi:10.1073/pnas.0404458101

Cited by 102Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

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Dolev, Iftach, Michaelson, Daniel M.·2004·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0404458101PMC PMC518852

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Abstract

The amyloid-β (Aβ) peptide, a major pathological hallmark of Alzheimer's disease (AD), undergoes a cascade of interactions resulting in the formation of soluble aggregates and their conversion in the brain to insoluble deposits and mature senile plaques. Furthermore, the apoE4 isoform of apolipoprotein E (apoE), which is the major genetic risk factor of AD, is associated with increased Aβ deposition. It is not known how the different Aβ aggregates in the amyloid cascade are formed, contribute to the pathogenesis of AD, or are affected by apoE4. To investigate the initial aggregation stages underlying the amyloid cascade in vivo and how apoE affects them, we examined the effects of prolonged inhibition and subsequent reactivation of the Aβ-degrading protease neprilysin on deposition, disaggregation, and fibrillization of Aβ in apoE-transgenic and control mice. In control mice, intracerebroventricular infusion of thiorphan, which inhibits neprilysin, induced Aβ42 and Aβ40 deposition and fibrillization. On termination of thiorphan treatment, the number of Aβ deposits decreased, whereas the fibrillar Aβ deposits were unaffected. Similar treatments in apoE-deficient mice and mice transgenic for human apoE4 or apoE3 revealed that apoE4 enhances specifically the nucleation and aggregation of immunopositive Aβ deposits and that reversible disaggregation of these deposits and their irreversible conversion to fibrillar deposits are stimulated similarly by the different apoE isoforms. Deposition of Aβ and its enhancement by apoE4 were accompanied by increased astrogliosis both far from and near the Aβ deposits, suggesting that astrogliosis might be triggered by both insoluble and soluble Aβ aggregates.

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Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition.
“Other studies using transgenic mice that possess different human apoE transgenes also demonstrate an isoform-specific difference (E4>E3) in Aβ deposition (Buttini et al., 2002; Dolev and Michaelson, 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Dolev and Michaelson, 2004

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Authors: Dolev, I., & Michaelson, D. M.
Affiliations: Tel Aviv University (IL)
ORCID: Michaelson, Daniel M.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2004-09-13
Volume: 101
Issue: 38
Pages: 13909-13914
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0404458101
PMC: PMC518852
OpenAlex: W2055425813
Cited by: 102
References: 13
Citations by year: 2026: 1 · 2025: 1 · 2024: 5 · 2023: 1 · 2022: 6 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 3 · 2012: 5
FWCI: 5.27
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Israel Academy of Sciences and Humanities
Tel Aviv University
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: amyloid-beta, Alzheimer's disease, apolipoprotein E, APOE ε4, amyloid hypothesis, neprilysin inhibition, thiorphan, amyloid-beta deposition, astrocyte activation, APOE isoforms
MeSH terms: Alzheimer Disease, Amyloid, Animals, Apolipoproteins E, Disease Models, Animal, Humans, Mice, Transgenic, Amyloid beta-Peptides, Mice

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A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

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