Amyloid β-protein affects cholesterol metabolism in cultured neurons: Implications for pivotal role of cholesterol in the amyloid cascade

Jian Sheng Gong, Naoya Sawamura, Kun Zou, Juro Sakai, Katsuhiko Yanagisawa, Makoto Michikawa

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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 β-protein (Aβ) promotes cholesterol release to form Aβ-lipid particles (Michikawa et al. [2001] J. Neurosci. 21:7226-7235). These lines of evidence inspired us to conduct further studies on whether Aβ affects cholesterol metabolism in neurons, which might lead to tau phosphorylation. Here, we report the effect of Aβ1-40 on cholesterol metabolism in cultured neurons prepared from rat cerebral cortex. Oligomeric Aβ1-40 inhibited cholesterol synthesis and reduced cellular cholesterol levels in a dose- and time-dependent manner, while freshly dissolved Aβ had no effect on cholesterol metabolism. However, oligomeric Aβ had no effect on the proteolysis of sterol regulatory element binding protein-2 (SREBP-2) or protein synthesis in cultured neurons. Oligomeric Aβ 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)aminomethy]fluorescein, hexaacetoxymethyl ester (calcein AM) staining, indicating that A& 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& alters cellular cholesterol homeostasis may provide new insight into the mechanism underlying the amyloid cascade hypothesis.

Original languageEnglish
Pages (from-to)438-446
Number of pages9
JournalJournal of Neuroscience Research
Volume70
Issue number3
DOIs
Publication statusPublished - 2002 Nov 2

Keywords

  • Alzheimer's disease
  • Amyloid ¢-protein
  • Cholesterol
  • Cholesterol release
  • Cholesterol synthesis
  • Tau phosphorylation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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