Elevated plasma cholesterol does not affect brain Aβ in mice lacking the low‐density lipoprotein receptor
Abstract
Epidemiological studies support an association between vascular risk factors, including hypercholesterolemia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolemia might directly promote beta-amyloid (Abeta) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances Abeta production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased Abeta production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences Abeta production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain Abeta40, Abeta42, or APP, or the Abeta42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR-/- mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain Abeta.
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Knockout mouse studies have provided direct evidence for LDLR and LRP1 as major apoE receptors in the brain.
“Knockout mouse studies have provided direct evidence for LDLR and LRP1 as major apoE receptors in the brain (Elder et al., 2007; Fryer et al., 2005; Liu et al., 2007).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Elder et al., 2007
LDLR deficiency does not affect endogenous murine Aβ levels in the brain.
“Recently, Buxbaum and colleagues also reported that LDLR deficiency did not affect endogenous murine Aβ levels in the brain (Elder et al., 2007).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Elder et al., 2007
LDLR deficiency significantly increases murine brain apoE levels by approximately 50%.
“Although LDLR deficiency significantly increased murine brain apoE levels by ~50%, it did not alter brain cholesterol levels (Elder et al., 2007; Fryer et al., 2005; Quan et al., 2003; Taha et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Elder et al., 2007
LDLR deficiency does not alter brain cholesterol levels.
“Although LDLR deficiency significantly increased murine brain apoE levels by ~50%, it did not alter brain cholesterol levels (Elder et al., 2007; Fryer et al., 2005; Quan et al., 2003; Taha et al., 2008).”
From Overexpression of Low-Density Lipoprotein Receptor in the Brain Markedly Inhibits Amyloid Deposition and Increases Extracellular Aβ Clearance (2009) · cites this paper as Elder et al., 2007
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“Interestingly, high dietary fat consumption has also been suggested to increase the risk of AD (Kalmijn et al. 1997).”
BackgroundLack of apolipoprotein E dramatically reduces amyloid β-peptide deposition
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Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases
Vance, J. E. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.010124 · Cited by 342 · see citing works
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Aberrant oligodendroglial LDL receptor orchestrates demyelination in chronic cerebral ischemia
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- Authors
- Elder, G. A., Cho, J. Y., English, D. F., Franciosi, S., Schmeidler, J., Sosa, M. A. G., Gasperi, R. D., Fisher, E. A., Mathews, P. M., Haroutunian, V., & Buxbaum, J. D.
- Affiliations
- James J. Peters VA Medical Center (US)
- Icahn School of Medicine at Mount Sinai (US)
- NYU Langone Health (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Buxbaum, Joseph D.
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2007-03-29
- Volume
- 102
- Issue
- 4
- Pages
- 1220-1231
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2093610690
- Cited by
- 26
- References
- 5
- Citations by year
- 2022: 1 · 2020: 1 · 2016: 1 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 3
- FWCI
- 3.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P01AG010491, AG010491, AG017617, AG002219, P01AG017617, P01AG002219)
- National Heart, Lung, and Blood Institute (R01HL084312, HL-084312)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- hypercholesterolemia, serum cholesterol, amyloid-beta, Alzheimer's disease, LDL receptor, Ldlr knockout mice, amyloid precursor protein, apolipoprotein E, brain cholesterol, high-fat diet, high-cholesterol diet, Aβ42/Aβ40 ratio, post-transcriptional regulation
- MeSH terms
- Analysis of Variance, Animals, Apolipoproteins E, Brain, Cholesterol, Male, Mice, Inbred C57BL, Peptide Fragments, Receptors, LDL, RNA, Messenger, Gene Expression, Amyloid beta-Peptides, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Mice
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