Enrichment of cholesterol in microdissected Alzheimer’s disease senile plaques as assessed by mass spectrometry

Abstract

Extensive knowledge of the protein components of the senile plaques, one of the hallmark lesions of Alzheimer’s disease, has been acquired over the years, but their lipid composition remains poorly known. Evidence suggests that cholesterol contributes to the pathogenesis of Alzheimer’s disease. However, its presence within senile plaques has never been ascertained with analytic methods. Senile plaques were microdissected from sections of the isocortex in three Braak VI Alzheimer’s disease cases and compared with a similar number of samples from the adjoining neuropil, free of amyloid-β peptide (Aβ) deposit. Two cases were apoε4/apoε3, and one case was apoε3/apoε3. A known quantity of 13C-labeled cholesterol was added to the samples as a standard. After hexane extraction, cholesterol content was analyzed by liquid chromatography coupled with electrospray ionization mass spectrometry. The mean concentration of free cholesterol was 4.25 ± 0.1 attomoles/µm3 in the senile plaques and 2.2 ± 0.49 attomoles/µm3 in the neuropil (t = 4.41, P < 0.0009). The quantity of free cholesterol per senile plaque (67 ± 16 femtomol) is similar to the published quantity of Aβ peptide. The highly significant increase in the cholesterol concentration, associated with the increased risk of Alzheimer’s disease linked to the apoε4 allele, suggests new pathogenetic mechanisms.

Keywords

• sterol
• brain tissue
• neurodegeneration
• apolipoprotein E
• lipoprotein receptor-related protein
• quantitative liquid chromatography coupled with mass spectrometry