Amyloid beta-protein affects cholesterol metabolism in cultured neurons: implications for pivotal role of cholesterol in the amyloid cascade.
Recently, we have found that alterations in cellular cholesterol metabolism are involved in promotion of tau phosphorylation (Fan et al. [2001] J. Neurochem. 76: 391-400; Sawamura et al. [2001] J. Biol. Chem. 276:10314-10319). In addition, we have shown that amyloid beta-protein (A beta) promotes cholesterol release to form A beta-lipid particles (Michikawa et al. [2001] J. Neurosci. 21:7226-7235). These lines of evidence inspired us to conduct further studies on whether A beta affects cholesterol metabolism in neurons, which might lead to tau phosphorylation. Here, we report the effect of A beta1-40 on cholesterol metabolism in cultured neurons prepared from rat cerebral cortex. Oligomeric A beta1-40 inhibited cholesterol synthesis and reduced cellular cholesterol levels in a dose- and time-dependent manner, while freshly dissolved A beta had no effect on cholesterol metabolism. However, oligomeric A beta had no effect on the proteolysis of sterol regulatory element binding protein-2 (SREBP-2) or protein synthesis in cultured neurons. Oligomeric A beta did not enhance lactate dehydrogenase (LDH) release from neuronal cells or decrease signals in the cultures reactive to 3,3'-Bis[N,N-bis(carboxymethyl)aminomethyl]fluorescein, hexaacetoxymethyl ester (calcein AM) staining, indicating that A beta used in this experiment did not cause neuronal death during the time course of our experiments. Since alterations in cholesterol metabolism induce tau phosphorylation, our findings that oligomeric A beta alters cellular cholesterol homeostasis may provide new insight into the mechanism underlying the amyloid cascade hypothesis.
Gong
Jian-Sheng
JS
Department of Dementia Research, National Institute for Longevity Sciences, Morioka, Obu, Japan.
Sawamura
Naoya
N
Zou
Kun
K
Sakai
Juro
J
Yanagisawa
Katsuhiko
K
Michikawa
Makoto
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006836:Hydro-Lyases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D002784:Cholesterol; D006836:Hydro-Lyases; C045581:lactate dehydratase