Neural HO-1/sterol interactions in vivo: Implications for Alzheimer's disease

J. R. Hascalovici; W. Song; A. Liberman; J. Vaya; S. Khatib; C. Holcroft; F. Laferla; H. M. Schipper

doi:10.1016/j.neuroscience.2014.09.001

Neural HO-1/sterol interactions in vivo: Implications for Alzheimer's disease

J. R. Hascalovici, W. Song, A. Liberman, J. Vaya, S. Khatib, C. Holcroft, F. Laferla, H. M. Schipper

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Background: Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. We previously provided evidence of significant HO-1/sterol interactions in vitro (cultured rat astroglia) and in post-mortem human AD brain (Religious Orders Study). Methods: The current experiments were designed to further delineate these interactions in vivo by comparing the behavior of HO-1/sterol interactions in two mouse models; (1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and (2) the previously described triple transgenic AD mouse (3xTg-AD). In samples of frontal cortex, total CH, CH precursors and relevant oxysterols were quantified by gas chromatography-mass spectrometry (GC-MS) and HO-1 protein expression was assessed by ELISA. The relationships of HO-1 expression to total CH, CH precursors and total oxysterols were determined for both mouse models using linear regression analysis. Results: HO-1 expression is increased in GFAP.HMOX1 mice relative to wild type and in 11-12-month-old 3xTg-AD mice (with AD-like phenotype) relative to control mice and 5-6-month-old 3xTg-AD mice (no AD-like phenotype). Total oxysterols significantly decreased as HO-1 expression increased in GFAP.HMOX1 mice expressing high levels of HO-1, whereas total oxysterols increased as HO-1 expression increased in aged 3xTg-AD mice. Total CH and total CH precursors increased as HO-1 protein expression increased in 11-12-month-old 3xTg-AD mice relative to 5-6-month old 3xTg-AD mice. Conclusions: Our findings indicate a differential impact of HO-1 on patterns of brain sterol and redox homeostasis that is contingent on the presence or absence of AD-like neuropathology. These data provide fresh insight concerning the regulation of sterol homeostasis within the aging and degenerating CNS which may inform the development of novel therapeutic and preventive strategies for the management of AD and related conditions.

Original language	English (US)
Pages (from-to)	40-49
Number of pages	10
Journal	Neuroscience
Volume	280
DOIs	https://doi.org/10.1016/j.neuroscience.2014.09.001
State	Published - Nov 7 2014
Externally published	Yes

Keywords

Alzheimer's disease
Astrocyte
Cholesterol
Heme oxygenase-1
Lipid
Oxysterol

ASJC Scopus subject areas

General Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.neuroscience.2014.09.001

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@article{a3533c36219d407cbdc5c90abf0d8a56,

title = "Neural HO-1/sterol interactions in vivo: Implications for Alzheimer's disease",

abstract = "Background: Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. We previously provided evidence of significant HO-1/sterol interactions in vitro (cultured rat astroglia) and in post-mortem human AD brain (Religious Orders Study). Methods: The current experiments were designed to further delineate these interactions in vivo by comparing the behavior of HO-1/sterol interactions in two mouse models; (1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and (2) the previously described triple transgenic AD mouse (3xTg-AD). In samples of frontal cortex, total CH, CH precursors and relevant oxysterols were quantified by gas chromatography-mass spectrometry (GC-MS) and HO-1 protein expression was assessed by ELISA. The relationships of HO-1 expression to total CH, CH precursors and total oxysterols were determined for both mouse models using linear regression analysis. Results: HO-1 expression is increased in GFAP.HMOX1 mice relative to wild type and in 11-12-month-old 3xTg-AD mice (with AD-like phenotype) relative to control mice and 5-6-month-old 3xTg-AD mice (no AD-like phenotype). Total oxysterols significantly decreased as HO-1 expression increased in GFAP.HMOX1 mice expressing high levels of HO-1, whereas total oxysterols increased as HO-1 expression increased in aged 3xTg-AD mice. Total CH and total CH precursors increased as HO-1 protein expression increased in 11-12-month-old 3xTg-AD mice relative to 5-6-month old 3xTg-AD mice. Conclusions: Our findings indicate a differential impact of HO-1 on patterns of brain sterol and redox homeostasis that is contingent on the presence or absence of AD-like neuropathology. These data provide fresh insight concerning the regulation of sterol homeostasis within the aging and degenerating CNS which may inform the development of novel therapeutic and preventive strategies for the management of AD and related conditions.",

keywords = "Alzheimer's disease, Astrocyte, Cholesterol, Heme oxygenase-1, Lipid, Oxysterol",

author = "Hascalovici, {J. R.} and W. Song and A. Liberman and J. Vaya and S. Khatib and C. Holcroft and F. Laferla and Schipper, {H. M.}",

note = "Publisher Copyright: {\textcopyright} 2014 IBRO.",

year = "2014",

month = nov,

day = "7",

doi = "10.1016/j.neuroscience.2014.09.001",

language = "English (US)",

volume = "280",

pages = "40--49",

journal = "Neuroscience",

issn = "0306-4522",

publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Neural HO-1/sterol interactions in vivo

T2 - Implications for Alzheimer's disease

AU - Hascalovici, J. R.

AU - Song, W.

AU - Liberman, A.

AU - Vaya, J.

AU - Khatib, S.

AU - Holcroft, C.

AU - Laferla, F.

AU - Schipper, H. M.

PY - 2014/11/7

Y1 - 2014/11/7

N2 - Background: Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. We previously provided evidence of significant HO-1/sterol interactions in vitro (cultured rat astroglia) and in post-mortem human AD brain (Religious Orders Study). Methods: The current experiments were designed to further delineate these interactions in vivo by comparing the behavior of HO-1/sterol interactions in two mouse models; (1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and (2) the previously described triple transgenic AD mouse (3xTg-AD). In samples of frontal cortex, total CH, CH precursors and relevant oxysterols were quantified by gas chromatography-mass spectrometry (GC-MS) and HO-1 protein expression was assessed by ELISA. The relationships of HO-1 expression to total CH, CH precursors and total oxysterols were determined for both mouse models using linear regression analysis. Results: HO-1 expression is increased in GFAP.HMOX1 mice relative to wild type and in 11-12-month-old 3xTg-AD mice (with AD-like phenotype) relative to control mice and 5-6-month-old 3xTg-AD mice (no AD-like phenotype). Total oxysterols significantly decreased as HO-1 expression increased in GFAP.HMOX1 mice expressing high levels of HO-1, whereas total oxysterols increased as HO-1 expression increased in aged 3xTg-AD mice. Total CH and total CH precursors increased as HO-1 protein expression increased in 11-12-month-old 3xTg-AD mice relative to 5-6-month old 3xTg-AD mice. Conclusions: Our findings indicate a differential impact of HO-1 on patterns of brain sterol and redox homeostasis that is contingent on the presence or absence of AD-like neuropathology. These data provide fresh insight concerning the regulation of sterol homeostasis within the aging and degenerating CNS which may inform the development of novel therapeutic and preventive strategies for the management of AD and related conditions.

AB - Background: Up-regulation of heme oxygenase-1 (HO-1) and altered cholesterol (CH) metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. We previously provided evidence of significant HO-1/sterol interactions in vitro (cultured rat astroglia) and in post-mortem human AD brain (Religious Orders Study). Methods: The current experiments were designed to further delineate these interactions in vivo by comparing the behavior of HO-1/sterol interactions in two mouse models; (1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and (2) the previously described triple transgenic AD mouse (3xTg-AD). In samples of frontal cortex, total CH, CH precursors and relevant oxysterols were quantified by gas chromatography-mass spectrometry (GC-MS) and HO-1 protein expression was assessed by ELISA. The relationships of HO-1 expression to total CH, CH precursors and total oxysterols were determined for both mouse models using linear regression analysis. Results: HO-1 expression is increased in GFAP.HMOX1 mice relative to wild type and in 11-12-month-old 3xTg-AD mice (with AD-like phenotype) relative to control mice and 5-6-month-old 3xTg-AD mice (no AD-like phenotype). Total oxysterols significantly decreased as HO-1 expression increased in GFAP.HMOX1 mice expressing high levels of HO-1, whereas total oxysterols increased as HO-1 expression increased in aged 3xTg-AD mice. Total CH and total CH precursors increased as HO-1 protein expression increased in 11-12-month-old 3xTg-AD mice relative to 5-6-month old 3xTg-AD mice. Conclusions: Our findings indicate a differential impact of HO-1 on patterns of brain sterol and redox homeostasis that is contingent on the presence or absence of AD-like neuropathology. These data provide fresh insight concerning the regulation of sterol homeostasis within the aging and degenerating CNS which may inform the development of novel therapeutic and preventive strategies for the management of AD and related conditions.

KW - Alzheimer's disease

KW - Astrocyte

KW - Cholesterol

KW - Heme oxygenase-1

KW - Lipid

KW - Oxysterol

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SN - 0306-4522

VL - 280

SP - 40

EP - 49

JO - Neuroscience

JF - Neuroscience

ER -

Neural HO-1/sterol interactions in vivo: Implications for Alzheimer's disease

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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