ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

Elena Y. Bryleva, Maximillian A. Rogers, Catherine C Y Chang, Floyd Buen, Brent T. Harris, Estelle Rousselet, Nabil G. Seidah, Salvatore Oddo, Frank M. Laferla, Thomas A. Spencer, William F. Hickey, Ta Yuan Chang

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD).Acyl-CoA:cholesterolacyltransferases (ACAT1andACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear.Herewe showthat ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the majoroxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP andHMGRprotein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.

Original languageEnglish (US)
Pages (from-to)3081-3086
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010
Externally publishedYes

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Amyloid
Alzheimer Disease
Pathology
Brain
Hydroxymethylglutaryl CoA Reductases
Genes
Cholesterol
Neurons
Acyl Coenzyme A
Cholesterol Esters
Sterols
Endoplasmic Reticulum
Neurodegenerative Diseases
Isoenzymes
Proteins
24-hydroxycholesterol
Enzymes
Therapeutics
Pharmaceutical Preparations

Keywords

  • Alzheimer disease
  • Cholesterol esterification
  • Lipid metabolism
  • Oxysterols

ASJC Scopus subject areas

  • General

Cite this

ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. / Bryleva, Elena Y.; Rogers, Maximillian A.; Chang, Catherine C Y; Buen, Floyd; Harris, Brent T.; Rousselet, Estelle; Seidah, Nabil G.; Oddo, Salvatore; Laferla, Frank M.; Spencer, Thomas A.; Hickey, William F.; Chang, Ta Yuan.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 16.02.2010, p. 3081-3086.

Research output: Contribution to journalArticle

Bryleva, EY, Rogers, MA, Chang, CCY, Buen, F, Harris, BT, Rousselet, E, Seidah, NG, Oddo, S, Laferla, FM, Spencer, TA, Hickey, WF & Chang, TY 2010, 'ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 7, pp. 3081-3086. https://doi.org/10.1073/pnas.0913828107
Bryleva, Elena Y. ; Rogers, Maximillian A. ; Chang, Catherine C Y ; Buen, Floyd ; Harris, Brent T. ; Rousselet, Estelle ; Seidah, Nabil G. ; Oddo, Salvatore ; Laferla, Frank M. ; Spencer, Thomas A. ; Hickey, William F. ; Chang, Ta Yuan. / ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 7. pp. 3081-3086.
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abstract = "Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD).Acyl-CoA:cholesterolacyltransferases (ACAT1andACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear.Herewe showthat ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60{\%} reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32{\%} content increase in 24-hydroxycholesterol (24SOH), the majoroxysterol in the brain. It also causes a 65{\%} protein content decrease in HMG-CoA reductase (HMGR) and a 28{\%} decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP andHMGRprotein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.",
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T1 - ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD

AU - Bryleva, Elena Y.

AU - Rogers, Maximillian A.

AU - Chang, Catherine C Y

AU - Buen, Floyd

AU - Harris, Brent T.

AU - Rousselet, Estelle

AU - Seidah, Nabil G.

AU - Oddo, Salvatore

AU - Laferla, Frank M.

AU - Spencer, Thomas A.

AU - Hickey, William F.

AU - Chang, Ta Yuan

PY - 2010/2/16

Y1 - 2010/2/16

N2 - Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD).Acyl-CoA:cholesterolacyltransferases (ACAT1andACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear.Herewe showthat ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the majoroxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP andHMGRprotein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.

AB - Cholesterol metabolism has been implicated in the pathogenesis of several neurodegenerative diseases, including the abnormal accumulation of amyloid-β, one of the pathological hallmarks of Alzheimer disease (AD).Acyl-CoA:cholesterolacyltransferases (ACAT1andACAT2) are two enzymes that convert free cholesterol to cholesteryl esters. ACAT inhibitors have recently emerged as promising drug candidates for AD therapy. However, how ACAT inhibitors act in the brain has so far remained unclear.Herewe showthat ACAT1 is the major functional isoenzyme in the mouse brain. ACAT1 gene ablation (A1-) in triple transgenic (i.e., 3XTg-AD) mice leads to more than 60% reduction in full-length human APPswe as well as its proteolytic fragments, and ameliorates cognitive deficits. At 4 months of age, A1- causes a 32% content increase in 24-hydroxycholesterol (24SOH), the majoroxysterol in the brain. It also causes a 65% protein content decrease in HMG-CoA reductase (HMGR) and a 28% decrease in sterol synthesis rate in AD mouse brains. In hippocampal neurons, A1- causes an increase in the 24SOH synthesis rate; treating hippocampal neuronal cells with 24SOH causes rapid declines in hAPP and in HMGR protein levels. A model is provided to explain our findings: in neurons, A1- causes increases in cholesterol and 24SOH contents in the endoplasmic reticulum, which cause reductions in hAPP andHMGRprotein contents and lead to amelioration of amyloid pathology. Our study supports the potential of ACAT1 as a therapeutic target for treating certain forms of AD.

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KW - Cholesterol esterification

KW - Lipid metabolism

KW - Oxysterols

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