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Cited by 294Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtease and Inhibitor Mechanisms

Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo

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Miller, Bonnie C., Eckman, Elizabeth A., Sambamurti, Kumar, Dobbs, Nicole, Chow, K. Martin, Eckman, Christopher B., Hersh, Louis B., Thiele, Dwain L.·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1031520100PMC PMC156353
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Abstract

Factors that elevate amyloid-β (Aβ) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in Aβ degradation based on its hydrolysis of Aβ peptides in vitro . In this study, in vivo levels of brain Aβ40 and Aβ42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the γ-secretase-generated C-terminal fragment of the Aβ precursor protein in the insulysin-deficient mouse also was found. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased ≈50%, brain Aβ peptides were increased to levels intermediate between those in wild-type mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. These findings indicate that there is an inverse correlation between in vivo insulysin activity levels and brain Aβ peptide levels and suggest that modulation of insulysin activity may alter the risk for Alzheimer's disease.

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  • Progression of Alzheimer's disease in humans and mouse models of the disease is associated with reduced expression of these Aβ-clearing enzymes resulting in decreased Aβ clearance and increased Aβ accumulation.

    “Progression of Alzheimer's disease in humans and mouse models of the disease is associated with reduced expression of these Aβ-clearing enzymes resulting in decreased Aβ clearance and increased Aβ accumulation (5, 24).”

    From Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice (2019) · cites this paper as [24]

    The Results and Discussion (page numbers unavailable) show that genetically reduced insulysin expression and activity in mice accompanied increased brain Aβ, and the authors infer that insulysin helps degrade Aβ in vivo. The paper does not establish that progression of Alzheimer’s disease in humans or disease-model mice is accompanied by declining expression of multiple Aβ-clearing enzymes; it suggests a possible link to disease risk instead. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Miller, B. C., Eckman, E. A., Sambamurti, K., Dobbs, N., Chow, K. M., Eckman, C. B., Hersh, L. B., & Thiele, D. L.
Affiliations
Mayo Clinic (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-05-05
Volume
100
Issue
10
Pages
6221-6226
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1031520100
PMC
PMC156353
OpenAlex
W2088608159
Cited by
294
References
3
Citations by year
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FWCI
13.44
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association
  • Mayo Foundation for Medical Education and Research
  • National Institutes of Health (n01da008801-000)
  • National Institute on Drug Abuse (N01 DA008801)
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 › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords
amyloid-beta, Alzheimer's disease, Aβ40, amyloid-beta 42, proteolytic activity, amyloid beta degradation, amyloid precursor protein
MeSH terms
Analysis of Variance, Animals, Base Sequence, Brain, Enzyme-Linked Immunosorbent Assay, Genotype, Insulysin, Kinetics, Mice, Inbred Strains, Amyloid beta-Peptides, DNA Primers, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Mice

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