LDL receptor knock-out mice show impaired spatial cognition with hippocampal vulnerability to apoptosis and deficits in synapses
Open accessAbstract
BACKGROUND: Evidence from clinical studies support the fact that abnormal cholesterol metabolism in the brain leads to progressive cognitive dysfunction. The low-density lipoprotein receptor (LDLR) is well-known for its role in regulating cholesterol metabolism. Whether LDLR involved in this impaired cognition and the potential mechanisms that underlie this impairment are unknown. METHODS: Twelve-month-old Ldlr-/- mice (n = 10) and wild-type littermates C57BL/6 J (n = 14) were subjected to the Morris water maze test. At 1 week after completion of the behavioural testing, all of the animals were sacrificed for analysis of synaptic and apoptotic markers. RESULTS: The plasma cholesterol concentration of Ldlr-/- mice was increased moderately when compared with C57BL/6 J mice (P < 0.05). Behavioural testing revealed that Ldlr-/- mice displayed impaired spatial memory, and moreover, the expression levels of synaptophysin and the number of synaptophysin-immunoreactive presynaptic boutons in the hippocampal CA1 and dentate gyrus were decreased (all P < 0.05). Ultrastructural changes in the dentate gyrus were observed using transmission electron microscopy. Furthermore, apoptosis in the hippocampus of Ldlr-/- mice was revealed based on elevation, at both the mRNA and protein levels, of the ratio of Bax/Bcl-2 expression (all P < 0.05)and an increase in activated-caspase3 protein level (P < 0.05). CONCLUSION: LDLR deficiency contributes to impaired spatial cognition. This most likely occurs via negative effects that promote apoptosis and synaptic deficits in the hippocampus.
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Despite apoptotic pathway upregulation, no structural alterations or shrinkage resulting from massive neuronal death has been observed in Ldlr−/− mice.
“Despite apoptotic pathway upregulation, no structural alterations or shrinkage resulting from massive neuronal death has been observed in this mutant mouse model [19].”
From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [19]
The Results and discussion (Electron microscopy; page unavailable) report structural alterations in the dentate gyrus of Ldlr−/− mice, including oedema, sparse neurofibrils and altered synapses. The same section reports elevated apoptosis-related markers, but the paper does not establish whether massive neuronal death caused shrinkage. (LLM, conf=0.86)
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Experimental — accuracy not yet measuredLDLR-deficient mice showed hippocampal apoptosis, decreased expression of synaptophysin and synaptic integrity, and consequent impairment of spatial cognition.
“Indeed, LDLR-deficient mice showed hippocampal apoptosis and decreased expression of the presynaptic protein synaptophysin and synaptic integrity in both hippocampal and dentate gyrus, with consequent impairment of spatial cognition [80]”
From The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer’s Disease: A Possible Target for the Disease Treatment (2024) · cites this paper as [80]
The Abstract (Results) reports impaired spatial memory, hippocampal apoptotic markers, reduced synaptophysin, and synaptic deficits in LDLR-deficient mice. The Abstract (Conclusion) says the cognitive impairment most likely occurs through apoptosis and synaptic deficits; it does not establish the causal link implied by “consequent impairment.” (LLM, conf=0.85)
Experimental — accuracy not yet measuredAbnormal cholesterol metabolism in the brain leads to progressive cognitive dysfunction.
“Some evidence from clinical studies support the fact that abnormal cholesterol metabolism in the brain leads to progressive cognitive dysfunction (Wang et al., 2014).”
From Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial (2016) · cites this paper as Wang et al., 2014
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“…and decreased expression of the presynaptic protein synaptophysin and synaptic integrity in both hippocampal and dentate gyrus, with consequent impairment of spatial cognition [80], reduced hippocampal cell proliferation and synapses formation [81], and signs of impaired learning and memory [82].”
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- Authors
- Wang, S.-H., Huang, Y., Yuan, Y., Xia, W.-Q., Wang, P., & Huang, R.
- Affiliations
- Yancheng First People's Hospital (CN)
- Zhongda Hospital Southeast University (CN)
- Venue
- Lipids in Health and Disease
- Published
- 2014-11-20
- Volume
- 13
- Issue
- 1
- Pages
- 175-175
- ISSN
- 1476-511X (ISSN-L)
- PMC
- PMC4258039
- OpenAlex
- W2170412514
- Cited by
- 44
- References
- 56
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 4 · 2015: 1
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Lipids in Health and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (BK2011601, 30870870, 81370921, 81070916)
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- LDL receptor, Ldlr knockout mice, spatial memory, hippocampus, apoptosis, synaptic loss, synaptophysin, presynaptic terminals, brain cholesterol metabolism, Bax/Bcl-2 ratio, caspase-3, dentate gyrus, cognitive impairment
- MeSH terms
- Animals, Cognition, Cognition Disorders, Male, Mice, Inbred C57BL, Receptors, LDL, Synapses, Gene Expression, Apoptosis, Mice, Knockout, Maze Learning, Apoptosis Regulatory Proteins, CA1 Region, Hippocampal
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