The DOI matches its Crossref record; 91 of the 92 references it cites were found in a registry or an index.
Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice
Open accessAbstract
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP) mRNA. Cleavage of AβPP can produce β-amyloid (Aβ), a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aβ is over-expressed in the brain of Fmr1(KO) mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1(KO) mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ(1-42) was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.
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“many of the other classic behavioural phenotypes used as outcome measures in preclinical studies are inconsistently observed in Fmr1-KO mice (such as open field, rotarod, elevated plus-maze, marble burying, self-grooming and most social paradigms).”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [65]
In the citing paper
“As a result, the rescue of these behavioural phenotypes has been difficult to consolidate and to use as a guide for clinical studies30,49,56,64,65.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [65]
In the citing paper
“Genetic reduction of AβPP in Fmr1 KO mice rescues characteristic FXS phenotypes, such as audiogenic seizures, the ratio of mature versus immature dendritic spines, and mGluR-LTD (91).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [91]
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Research works printed but not linked: 2
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Metadata
- Authors
- Westmark, C. J., Westmark, P. R., O'Riordan, K. J., Ray, B. C., Hervey, C. M., Salamat, M. S., Abozeid, S. H., Stein, K. M., Stodola, L. A., Tranfaglia, M., Burger, C., Berry-Kravis, E. M., & Malter, J. S.
- Affiliations
- University of Wisconsin–Madison (US)
- Rush University Medical Center (US)
- Fraxa Research Foundation (US)
- Corresponding author
- Westmark, Cara J.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-10-26
- Volume
- 6
- Issue
- 10
- Pages
- e26549
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3202540
- OpenAlex
- W1966255973
- Cited by
- 110
- References
- 92
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 9 · 2016: 13 · 2015: 16 · 2014: 13 · 2013: 11 · 2012: 8
- FWCI
- 6.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- FRAXA Research Foundation
- Waisman Center (P30 HD03352, HD03352)
- National Institutes of Health (HD033.52)
- National Institute on Drug Abuse (R01DA026067)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD03352., P30HD003352)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- fragile X syndrome, FMRP, amyloid precursor protein, amyloid-beta, Fmr1 knockout mice, audiogenic seizures, anxiety, dendritic spines, metabotropic glutamate receptors, long-term depression, plasma biomarkers, intellectual disability, autism spectrum disorder, Alzheimer's disease
- MeSH terms
- Animals, Brain Chemistry, Female, Fragile X Syndrome, Male, Neurons, Peptide Fragments, Phenotype, Genetic Therapy, Down-Regulation, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Receptors, Metabotropic Glutamate, Mice, Knockout, Dendritic Spines, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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