Abstract
BackgroundEvidence 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.MethodsTwelve-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.ResultsThe 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).ConclusionLDLR deficiency contributes to impaired spatial cognition. This most likely occurs via negative effects that promote apoptosis and synaptic deficits in the hippocampus.
Highlights
Alzheimer’s disease (AD) is characterised by extracellular amyloid plaques, intra-neuronal neurofibrillary tangles, cerebrovascular amyloid deposits and a loss of neurons and synapses in specific brain regions [1,2]
Repeated measures analysis of variance (ANOVA) showed significant effects of Ldlr deficiency on the reduced percentage of time spent swimming in the target quadrant (F(3,66) = 10.90, P = 0.01) (Figure 2D), showing a poorer learning performance
Typical swimming patterns observed on day 4 of the training period suggested that C57BL/6 J mice found the platform primarily by tendency and linear patterns, whereas the Ldlr−/− mice swam at the margins, and the swimming patterns were random (Figure 2E)
Summary
At 1 week after completion of the behavioural testing, all of the animals were sacrificed for analysis of synaptic and apoptotic markers
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