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Increased soluble amyloid-β peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein
Open accessAbstract
Amyloid-β peptide (Aβ) is central to the pathogenesis of Alzheimer's disease, and the low-density lipoprotein receptor-related protein (LRP) has been shown to alter Aβ metabolism in vitro . Here, we show that overexpression of a functional LRP minireceptor in the brain of PDAPP mice results in age-dependent increase of soluble brain Aβ, with no changes in Aβ plaque burden. Importantly, soluble brain Aβ was found to be primarily in the form of monomers/dimers and to be highly correlated with deficits in spatial learning and memory. These results provide in vivo evidence that LRP may contribute to memory deficits typical of Alzheimer's disease by modulating the pool of small soluble forms of Aβ.
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“overexpression of a functional LRP1 minireceptor resulted in a 25% reduction of brain apoE levels, there was an age-dependent increase of soluble Aβ in the brain of PDAPP transgenic mice”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Zerbinatti et al 2004
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In the citing paper
“Although an ~25% reduction in brain apoE levels was observed in LRP1 transgenic mice, there was an increase in soluble and insoluble Aβ in old mice (Zerbinatti et al., 2006; Zerbinatti 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 Zerbinatti et al., 2004
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In the citing paper
“LRP overexpression in APP V717F mice, besides augmenting intraneuronal Ab accumulation, exacerbated the memory deficit and caused an increase in soluble Ab level in the brain.41”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [41]
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In the citing paper
“However, the transgene product was not full-length LRP and the transgene was not expressed by its endogenous promoter.”
From Receptor-Associated Protein (RAP) Plays a Central Role in Modulating Aβ Deposition in APP/PS1 Transgenic Mice (2008) · cites this paper as [24]
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“In a direct test of the role of LRP in amyloidogenesis, transgenic mice that overexpress an LRP-minireceptor, containing the ligand-binding domain II of human LRP and the region representing the transmembrane subunit including the full cytoplasmic tail (mLRP2), were mated to PDAPP mice [24].”
From Receptor-Associated Protein (RAP) Plays a Central Role in Modulating Aβ Deposition in APP/PS1 Transgenic Mice (2008) · cites this paper as [24]
In the citing paper
“The authors reported 3-fold increases in LRP levels and found increased soluble Aβ and enhanced memory impairment in PDAPP mice, but did not find evidence of a change in amyloid loads in mice harboring both transgenes as compared to mice harboring only the PDAPP transgene.”
From Receptor-Associated Protein (RAP) Plays a Central Role in Modulating Aβ Deposition in APP/PS1 Transgenic Mice (2008) · cites this paper as [24]
In the citing paper
“Zerbinatti et al. [24] reported that overexpression of an LRP minireceptor in the PDAPP mouse model of AD, resulted in increased levels of soluble Aβ but did not impact amyloid burden.”
From Receptor-Associated Protein (RAP) Plays a Central Role in Modulating Aβ Deposition in APP/PS1 Transgenic Mice (2008) · cites this paper as [24]
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Metadata
- Authors
- Zerbinatti, C. V., Wozniak, D. F., Cirrito, J., Cam, J. A., Osaka, H., Bales, K. R., Zhuo, M., Paul, S. M., Holtzman, D. M., & Bu, G.
- Affiliations
- University of Toronto (CA)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-01-19
- Volume
- 101
- Issue
- 4
- Pages
- 1075-1080
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC327153
- OpenAlex
- W2007048586
- Cited by
- 133
- References
- 43
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 8 · 2016: 5 · 2015: 3 · 2014: 4 · 2013: 9 · 2012: 12
- FWCI
- 7.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (AG11355, P 50 AG05681, P50AG005681, P01AG011355)
- National Institute of Neurological Disorders and Stroke (NS41872, F32NS041872)
- 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
- amyloid-beta, soluble amyloid-beta, low density lipoprotein receptor-related protein, Alzheimer's disease, memory impairment, spatial learning, PDAPP mice, amyloid-beta metabolism, brain
- MeSH terms
- Animals, Brain, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Memory Disorders, Mice, Inbred C3H, Solubility, Amyloid beta-Peptides, LDL-Receptor Related Proteins, Mice
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