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

Abstract

The core of the SP is made of aggregated amyloid-␤ (A ␤ ) peptide. A ␤ peptide is cleaved from a type 1 transmembrane protein, the amyloid protein precursor (APP), by the sequential activities of the ␤ and ␥ secretases. Special staining of microscopic sections from brain samples of AD patients has long suggested that SPs were enriched in lipids ( 5 ). The presence of cholesterol among those lipids is plausible since apolipoprotein E (apoE), a transporter of cholesterol, has been found in the SPs by immunohistochemistry ( 6, 7 ). The apo 4 allele is currently considered as the risk factor best associated with AD ( 8 ). Although the role of cholesterol has remained elusive, a much debated meta-analysis has shown that the use of statins, which inhibit cholesterol synthesis, was associated with a decreased prevalence of AD ( 9, 10 ). In cell cultures, the interaction between APP and cholesterol metabolism has been found so intricate that APP has been considered a sensor modulating the cholesterol content of the cell membrane ( 11 ).Histological studies have apparently confi rmed the cholesterol enrichment of the SPs in transgenic mice and AD patients ( 12 ). Two methods have been used. 1 ) Filipin, a well-known fl uorescent probe of membrane cholesterol, labels the SPs and subsequently resists the photobleaching that rapidly decreases the fl uorescence of the surrounding tissue. 2 ) An enzymatic technique based upon cholesterol oxidase activity was initially devised (and commercialized) for colorometric cholesterol assay (not for histochemistry). It is based on the oxidation of Amplex Red ® (10-acetyl-3,7-dihydroxyphenoxazine) into brightly fl uorescent resorufi n. Press, September 18, 2009 DOI 10.1194 Abbreviations: A ␤ , amyloid-␤ peptide; AD, Alzheimer's disease; apoE, apolipoprotein E; APP, amyloid protein precursor; LCM, laser capture microdissection; LC-MS, liquid chromatography coupled with mass spectrometry; LRP, low density lipoprotein receptor-related protein; SP, senile plaque. Published, JLR Papers in

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