Abstract
Apolipoprotein E4 (ApoE4), one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD). ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF) diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT), human ApoE4 and ApoE-knockout (ApoE-/-) mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol) throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009). HF diet improved spatial learning in WT mice (p = 0.045), but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68) in the cornu ammonis 1 (CA1) region in ApoE4 (p = 0.001) and in ApoE-/- (p = 0.032) mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052), while it decreased in ApoE4 (p = 0.009), but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX) was found in both ApoE4 (p = 0.052) and ApoE-/- mice (p = 0.068). In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice.
Highlights
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer disease (AD)
ApoE-/- mice displayed a trend for increased time spent in platform area (p = 0.059) in the first 30 seconds of the probe phase (Fig 3D)
It appears that a HF diet reduces signs of neurodegeneration in ApoE4 mice and to a lesser extend in ApoE-/- mice, while it may increase signs of neurodegeneration in WT mice
Summary
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer disease (AD). Carriers of ApoE4 have a much higher prevalence and earlier age of onset of Alzheimer disease (AD) than non-carriers. Cardiovascular disease, type 2 diabetes mellitus, hypertension and a high fat intake at middle age all have been identified as risk factors for cerebrovascular disease including AD. All of these factors can be aggravated by a sedentary lifestyle and a high-fat intake [7,8,9,10]. Another study showed that decreased CBF in patients with metabolic syndrome, a collection of cardiovascular risk factors including high triglyceride and low HDL cholesterol levels is associated with impaired cognition [14]. Zerbi et al have shown that ApoE4 and ApoE knockout mouse models display reduced CBF [15]
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