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 (A β) deposit. Two cases were apo α 4/apo α 3, and one case was apo α 3/apo α 3. A known quantity of 13 C-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/ μ 3 in the senile plaques and 2.2 ± 0.49 attomoles/μm 3 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 A β peptide. The highly signifi-cant increase in the cholesterol concentration, associated with the increased risk of Alzheimer's disease linked to the apo α 4 allele, suggests new pathogenetic mechanisms. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.