Potential mechanisms linking cholesterol to Alzheimer's disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle

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Abstract

Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Aβ in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-β protein precursor (AβPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Aβ levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.

Original languageEnglish (US)
Pages (from-to)673-684
Number of pages12
JournalJournal of Alzheimer's Disease
Volume15
Issue number4
DOIs
StatePublished - Jan 1 2008

Fingerprint

Alzheimer Disease
Skeletal Muscle
Cholesterol
Pathology
Rabbits
Brain
Inclusion Body Myositis
Aptitude
Amyloid beta-Protein Precursor
Hypercholesterolemia
Amyloid
Peptides

Keywords

  • 27-hydroxycholesterol
  • ATP-binding cassette transporters
  • Alzheimer's disease
  • Amyloid-β
  • Blood brain barrier
  • Cholesterol
  • Inclusion body myositis
  • Rabbit

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

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title = "Potential mechanisms linking cholesterol to Alzheimer's disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle",
abstract = "Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Aβ in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-β protein precursor (AβPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Aβ levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.",
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N2 - Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Aβ in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-β protein precursor (AβPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Aβ levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.

AB - Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are important in the pathogenesis of Alzheimer's disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Aβ in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Previous and ongoing work from our laboratory indicates that hypercholesterolemia leads to the increased neuronal content of cholesterol and increased levels and processing of the amyloid-β protein precursor (AβPP). We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, increases Aβ levels in both organotypic hippocampal slices and in neuronal preparations cultured from adult rabbits. This cholesterol metabolite is predominantly formed in the circulation and, in contrast to cholesterol, has the ability to cross into the brain. These results may indicate that 27-hydroxycholesterol is the link between circulating cholesterol and AD-like pathology in the brain. We also have found pathological hallmarks in the skeletal muscle of cholesterol-fed rabbits that are suggestive of inclusion body myositis, a disease that shares some pathological similarities with AD.

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