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Neuronal LRP1 Knockout in Adult Mice Leads to Impaired Brain Lipid Metabolism and Progressive, Age-Dependent Synapse Loss and Neurodegeneration
Open accessAbstract
The vast majority of Alzheimer's disease (AD) cases are late onset with progressive synapse loss and neurodegeneration. Although the amyloid hypothesis has generated great insights into the disease mechanism, several lines of evidence indicate that other risk factors might precondition the brain to amyloid toxicity. Here, we show that the deletion of a major lipoprotein receptor, low-density lipoprotein receptor-related protein 1 (LRP1), in forebrain neurons in mice leads to a global defect in brain lipid metabolism characterized by decreased brain levels of cholesterol, sulfatide, galactosylceramide, and triglyceride. These lipid deficits correlate with progressive, age-dependent dendritic spine degeneration, synapse loss, neuroinflammation, memory loss, and eventual neurodegeneration. We further show that the levels of glutamate receptor subunits NMDA receptor 1 and Glu receptor 1 are selectively reduced in LRP1 forebrain knock-out mice and in LRP1 knockdown neurons, which is partially rescued by restoring neuronal cholesterol. Together, these studies support a critical role for LRP1 in maintaining brain lipid homeostasis and associated synaptic and neuronal integrity, and provide important insights into the pathophysiological mechanisms in AD.
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“On the other hand, the cholesterol depletion hypothesis is in full accordance with the results of in vivo animal studies, in which silencing of lipoprotein receptors, implicated in cholesterol uptake and target of PCSK9, led to cognitive impairment [55,56,57,58,59], which was likely related to neuronal loss.”
From PCSK9 affects astrocyte cholesterol metabolism and reduces neuron cholesterol supplying in vitro: potential implications in Alzheimer’s disease (2022) · cites this paper as [55]
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“at the age of 9 months, when LRP1 is sufficiently deleted ( 17”
From APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1 (2019) · cites this paper as [17]
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“LRP1 belongs to the same family as LRP5 and is known to regulate crucial processes that help maintain synaptic integrity and cholesterol homeostasis in the brain.[44][45][46]”
From Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function (2024) · cites this paper as [44]
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“Defects in this protein result in degeneration of dendritic spines and synapses and in neuroinflammation [100].”
From Loss of Mevalonate/Cholesterol Homeostasis in the Brain: A Focus on Autism Spectrum Disorder and Rett Syndrome (2019) · cites this paper as [100]
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“In line with this notion, lower (rather than higher) sulfatide levels were observed in another mouse model with neuron-specific LRP1 deficiency previously (Liu et al., 2010).”
From The Pro-Neurotrophin Receptor Sortilin Is a Major Neuronal Apolipoprotein E Receptor for Catabolism of Amyloid-β Peptide in the Brain (2013) · cites this paper as Liu et al., 2010
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“It has been reported that the deletion of Lrp1 driven by CaMKII-Cre was significant in the cortex and hippocampus after 6 months of age [39].”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [39]
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“Cholesterol is essential for neurons, because a lack of cholesterol leads to synapse degeneration, impaired synaptic vesicle exocytosis and neurotransmission, and overall decreased neuronal activity.[42][43][44]”
From Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function (2024) · cites this paper as [44]
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Metadata
- Authors
- Liu, Q., Trotter, J., Zhang, J., Peters, M. M., Cheng, H., Bao, J., Han, X., Weeber, E. J., & Bu, G.
- Affiliations
- Washington University in St. Louis (US)
- University of South Florida (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-12-15
- Volume
- 30
- Issue
- 50
- Pages
- 17068-17078
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3146802
- OpenAlex
- W2032607393
- Cited by
- 268
- References
- 53
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 17 · 2023: 29 · 2022: 34 · 2021: 14 · 2020: 22 · 2019: 14 · 2018: 7 · 2017: 19 · 2016: 14 · 2015: 17 · 2014: 18 · 2013: 13 · 2012: 9
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Alzheimer's Association
- American Health Assistance Foundation
- Hope Center for Neurological Disorders
- National Institutes of Health
- National Institute on Aging (P01AG030128, R01AG031675, R01AG027924, R01 AG02792405, R01AG031784, R01AG035355)
- National Institute on Deafness and Other Communication Disorders (R21DC010489)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- LRP1, Alzheimer's disease, brain lipid metabolism, synaptic loss, neurodegeneration, neuroinflammation, memory loss, NMDA receptor 1, GluR1, lipoprotein receptors, forebrain neurons, age-related neurodegeneration
- MeSH terms
- Age Factors, Amnesia, Animals, Hippocampus, Nerve Degeneration, Neurons, Synapses, Receptors, N-Methyl-D-Aspartate, Prosencephalon, Receptors, AMPA, Mice, Knockout, Cell Culture Techniques, Low Density Lipoprotein Receptor-Related Protein-1, Dendritic Spines, Lipid Metabolism, Mice
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