Abstract
BackgroundStrong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. A key regulator of cholesterol transport is the Apolipoprotein E4 (ApoE4), which plays a fundamental role in neuronal maintenance and repair. Impaired function of ApoE4 may contribute to altered cerebral metabolism leading to higher susceptibility to neurodegeneration.MethodsTo determine a possible link between ApoE function and alterations in AD in the brain of Apolipoprotein E-deficient mice (ApoE−/−) in a longitudinal manner metabolic and neurochemical parameters were analyzed. Cortical metabolism was measured by 2-deoxy-2-[18F]fluoroglucose ([18F]FDG)-PET/CT and proton magnetic resonance spectroscopy (1H-MRS) served to record neurochemical status.ResultsBy using [18F]FDG-PET/CT, we showed that brain metabolism declined significantly stronger with age in ApoE−/− versus wild type (wt) mice. This difference was particularly evident at the age of 41 weeks in almost each analyzed brain region. In contrast, the 1H-MRS-measured N-acetylaspartate to creatine ratio, a marker of neuronal viability, did not decline with age and did not differ between ApoE−/− and wt mice.ConclusionIn summary, this longitudinal in vivo study shows for the first time that ApoE−/− mice depict cerebral hypometabolism without neurochemical alterations.
Highlights
A strong line of evidence suggests that the increased risk to develop Alzheimer’s disease (AD) may at least be partly mediated by cholesterol metabolism [3]
The Apolipoprotein E4 (ApoE4) genotype is associated with reduced cortical metabolism in AD predilection sites, such as the posterior cingulate gyrus
Reiman et al [16] found that the human APOEɛ4 gene dose correlated with [18F]FDG-PET/CT measurements of hypometabolism in AD-affected brain regions in a cognitively normal cohort, and postulated to use PET/CT as a pre-symptomatic endophenotype to help assess putative modifiers of AD risk
Summary
Strong line of evidence suggests that the increased risk to develop AD may at least be partly mediated by cholesterol metabolism. ApoE is the most prevalent brain apolipoprotein and plays a fundamental role in neuronal. The ApoE4 genotype is associated with reduced cortical metabolism in AD predilection sites, such as the posterior cingulate gyrus. Reiman et al [16] found that the human APOEɛ4 gene dose correlated with [18F]FDG-PET/CT measurements of hypometabolism in AD-affected brain regions in a cognitively normal cohort, and postulated to use PET/CT as a pre-symptomatic endophenotype to help assess putative modifiers of AD risk. [18F]FDG-PET/CT is a widely used tool in pre-clinical studies investigating AD pathology [17]. A pre-clinical study reported that mice carrying the human APOE 4 isoform (hApoE4-TR) showed decreased [18F]FDG uptake [18]. Decreased levels of NAA may reflect alterations of neuronal functional viability. Since alterations in NAA can be detected before the clinical appearance of dementia [22, 23], reduced NAA level may potentially serve as an early biomarker [24, 25]
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