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-beta peptide (A beta) deposit. Two cases were apo epsilon 4/apo epsilon 3, and one case was apo epsilon 3/apoepsilon3. 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/microm(3) in the
senile plaques and 2.2 +/- 0.49 attomoles/microm(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 beta
peptide. The highly significant increase in the
cholesterol concentration, associated with the increased risk of
Alzheimer's disease linked to the apo epsilon 4 allele, suggests new pathogenetic mechanisms.