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

46 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
Externally publishedYes

Fingerprint

Amyloidogenic Proteins
Amyloid
Cholesterol
Neurons
Phosphorylation
Sterol Regulatory Element Binding Protein 2
Serum Amyloid A Protein
Fluorescein
L-Lactate Dehydrogenase
Cerebral Cortex
Proteolysis
Cause of Death
Esters
Homeostasis
Staining and Labeling
Lipids

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Amyloid β-protein affects cholesterol metabolism in cultured neurons : Implications for pivotal role of cholesterol in the amyloid cascade. / Gong, Jian Sheng; Sawamura, Naoya; Zou, Kun; Sakai, Juro; Yanagisawa, Katsuhiko; Michikawa, Makoto.

In: Journal of Neuroscience Research, Vol. 70, No. 3, 02.11.2002, p. 438-446.

Research output: Contribution to journalArticle

Gong, Jian Sheng ; Sawamura, Naoya ; Zou, Kun ; Sakai, Juro ; Yanagisawa, Katsuhiko ; Michikawa, Makoto. / Amyloid β-protein affects cholesterol metabolism in cultured neurons : Implications for pivotal role of cholesterol in the amyloid cascade. In: Journal of Neuroscience Research. 2002 ; Vol. 70, No. 3. pp. 438-446.
@article{e50bcf79856b4b86ba428f3b86a2e180,
title = "Amyloid β-protein affects cholesterol metabolism in cultured neurons: Implications for pivotal role of cholesterol in the amyloid cascade",
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.",
keywords = "Alzheimer's disease, Amyloid ¢-protein, Cholesterol, Cholesterol release, Cholesterol synthesis, Tau phosphorylation",
author = "Gong, {Jian Sheng} and Naoya Sawamura and Kun Zou and Juro Sakai and Katsuhiko Yanagisawa and Makoto Michikawa",
year = "2002",
month = "11",
day = "2",
doi = "10.1002/jnr.10347",
language = "English",
volume = "70",
pages = "438--446",
journal = "Journal of Neuroscience Research",
issn = "0360-4012",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Amyloid β-protein affects cholesterol metabolism in cultured neurons

T2 - Implications for pivotal role of cholesterol in the amyloid cascade

AU - Gong, Jian Sheng

AU - Sawamura, Naoya

AU - Zou, Kun

AU - Sakai, Juro

AU - Yanagisawa, Katsuhiko

AU - Michikawa, Makoto

PY - 2002/11/2

Y1 - 2002/11/2

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Amyloid ¢-protein

KW - Cholesterol

KW - Cholesterol release

KW - Cholesterol synthesis

KW - Tau phosphorylation

UR - http://www.scopus.com/inward/record.url?scp=0037010287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037010287&partnerID=8YFLogxK

U2 - 10.1002/jnr.10347

DO - 10.1002/jnr.10347

M3 - Article

C2 - 12391604

AN - SCOPUS:0037010287

VL - 70

SP - 438

EP - 446

JO - Journal of Neuroscience Research

JF - Journal of Neuroscience Research

SN - 0360-4012

IS - 3

ER -