Apolipoprotein E and Low Density Lipoprotein Receptor-related Protein Facilitate Intraneuronal Aβ42 Accumulation in Amyloid Model Mice
Open accessAbstract
The low density lipoprotein receptor-related protein (LRP) is highly expressed in the brain and has been shown to alter the metabolism of amyloid precursor protein and amyloid-beta peptide (Abeta) in vitro. Previously we developed mice that overexpress a functional LRP minireceptor (mLRP2) in their brains and crossed them to the PDAPP mouse model of Alzheimer disease. Overexpression of mLRP2 in 22-month-old PDAPP mice with amyloid plaques increased a pool of carbonate-soluble Abeta in the brain and worsened memory-related behavior. In the current study, we examined the effects of mLRP2 overexpression on 3-month-old PDAPP mice that had not yet developed amyloid plaques. We found significantly higher levels of membrane-associated Abeta42 in the hippocampus of mice that overexpressed mLRP2. Using immunohistochemical methods, we observed significant intraneuronal Abeta42 in the hippocampus and frontal cortex of PDAPP mice, which frequently co-localized with the lysosomal marker LAMP-1. Interestingly, PDAPP mice lacking apolipoprotein E (apoE) had much less intraneuronal Abeta42. We also found that PC12 cells overexpressing mLRP2 cleared Abeta42 and Abeta40 more rapidly from media than PC12 cells transfected with the vector only. Preincubation of apoE3 or apoE4 with Abeta42 increased the rate of Abeta clearance, and this effect was partially blocked by receptor-associated protein. Our results support the hypothesis that LRP binds and endocytoses Abeta42 both directly and via apoE…
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In LRP1 transgenic mice, an ~25% reduction in brain apoE levels was observed, but there was an increase in soluble and insoluble Aβ in old mice.
“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., 2006
ApoE promotes neuronal Aβ uptake.
“The propensity of ApoE to bind Ab and its efficient internalization by neurons implicates ApoE in promoting neuronal Ab uptake.15”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [15]
Overexpression of LRP in several neuronal cell lines resulted in increased intraneuronal Aβ accumulation.
“Overexpression of low-density lipoprotein receptor-related protein (LRP) in several neuronal cell lines resulted in increased intraneuronal Ab accumulation.15,40”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [15]
In APP V717F mice, ApoE knockout was reported to cause a marked reduction in intraneuronal Aβ accumulation.
“Similar to observations in APP SW /PS1 dE9 /ApoE KO mice, KO of ApoE in APP V717F mice was also reported to cause marked reduction in the intraneuronal Ab accumulation.15”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [15]
Modulating LRP1 has been reported to affect brain apoE levels.
“Modulating LRP1 has also been reported to affect brain apoE levels (Liu et al., 2007; Zerbinatti et al., 2006)”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Zerbinatti et al., 2006
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“The propensity of ApoE to bind Ab and its efficient internalization by neurons implicates ApoE in promoting neuronal Ab uptake.(15) To characterize the role of ApoE in intraneuronal Ab accumulation and to test the hypothesis that a therapeutic agent blocking the ApoE/Ab binding could ameliorate intraneuronal Ab buildu…”
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- Authors
- Zerbinatti, C. V., Wahrle, S. E., Kim, H., Cam, J. A., Bales, K., Paul, S. M., Holtzman, D. M., & Bu, G.
- Affiliations
- Washington University in St. Louis (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Bu, Guojun
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 281
- Issue
- 47
- Pages
- 36180-36186
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2041371648
- Cited by
- 129
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 6 · 2016: 11 · 2015: 4 · 2014: 11 · 2013: 9 · 2012: 7
- FWCI
- 7.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (R01AG027924)
- National Institute of Neurological Disorders and Stroke (F32-NS41872, F32NS041872)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, low density lipoprotein receptor-related protein, amyloid-beta 42, amyloid plaques, PDAPP mice, Alzheimer's disease, amyloid clearance, lysosomes, LAMP1, receptor-associated protein, APOE3, APOE ε4, hippocampus, frontal cortex, memory impairment
- MeSH terms
- Animals, Apolipoproteins E, Brain, Endocytosis, Hippocampus, Humans, Immunohistochemistry, Lysosomes, Mice, Transgenic, Neurons, Peptide Fragments, Amyloid beta-Peptides, PC12 Cells, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Rats
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