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The Journal of Neuroscience, September 15, 2001, 21(18):7226-7235
A Novel Action of Alzheimer's Amyloid  -Protein (A):
Oligomeric A Promotes Lipid Release
Makoto
Michikawa,
Jian-Sheng
Gong,
Qi-Wen
Fan,
Naoya
Sawamura, and
Katsuhiko
Yanagisawa
Department of Dementia Research, National Institute for Longevity
Sciences, Obu, Aichi 474-8522, Japan
Interactions between amyloid  -protein (A) and lipids have
been suggested to play important roles in the pathogenesis of Alzheimer's disease. However, the molecular mechanism underlying these
interactions has not been fully understood. We examined the effect of
A on lipid metabolism in cultured neurons and astrocytes and found
that oligomeric A, but not monomeric or fibrillar A, promoted
lipid release from both types of cells in a dose- and time-dependent
manner. The main components of lipids released after the addition of
A were cholesterol, phospholipids, and monosialoganglioside (GM1).
Density-gradient and electron microscopic analyses of the conditioned
media demonstrated that these A and lipids formed particles and were
recovered from the fractions at densities of ~1.08-1.18 g/ml, which
were similar to those of high-density lipoprotein (HDL) generated by
apolipoproteins. The lipid release mediated by A was abolished by
concomitant treatment with Congo red and the PKC inhibitor, H7, whereas
it was not inhibited with
N-acetyl-L-cysteine. These A-lipid
particles were not internalized into neurons, whereas HDL-like
particles produced by apolipoprotein E were internalized. Our findings
indicate that oligomeric A promotes lipid release from neuronal
membrane, which may lead to the disruption of neuronal lipid
homeostasis and the loss of neuronal function.
Key words:
amyloid -protein; cholesterol release; phospholipid; high-density lipoprotein; cultured neurons; Alzheimer's disease
Copyright © 2001 Society for Neuroscience 0270-6474/01/21187226-10$05.00/0
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