Cholesterol and Alzheimer's disease

Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors

Kumar Sambamurti, Ann Charlotte Granholm, Mark S. Kindy, Narayan R. Bhat, Nigel H. Greig, Debomoy Lahiri, Jacobo E. Mintzer

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (AP) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Aβ or non-amyloid proteins. However, the mechanisms of neurotoxicity of Aβ and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the E4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Aβ has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

Original languageEnglish
Pages (from-to)517-528
Number of pages12
JournalCurrent Drug Targets
Volume5
Issue number6
DOIs
StatePublished - Aug 2004

Fingerprint

Alzheimer Disease
Theoretical Models
Cholesterol
Protein Precursors
Apolipoproteins E
Presenilin-2
Presenilin-1
Lipids
Amyloid Precursor Protein Secretases
Microtubule-Associated Proteins
Poisons
Amyloid beta-Peptides
Genetically Modified Animals
Amyloid Plaques
Brain
Animals
Genes
Cultured Cells
Cells
Alleles

Keywords

  • Aging
  • Apolipoprotein E
  • Cognition
  • Dementia
  • Diets
  • High fats
  • Memory
  • Myelin
  • Secretase

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

Cite this

Cholesterol and Alzheimer's disease : Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors. / Sambamurti, Kumar; Granholm, Ann Charlotte; Kindy, Mark S.; Bhat, Narayan R.; Greig, Nigel H.; Lahiri, Debomoy; Mintzer, Jacobo E.

In: Current Drug Targets, Vol. 5, No. 6, 08.2004, p. 517-528.

Research output: Contribution to journalArticle

Sambamurti, Kumar ; Granholm, Ann Charlotte ; Kindy, Mark S. ; Bhat, Narayan R. ; Greig, Nigel H. ; Lahiri, Debomoy ; Mintzer, Jacobo E. / Cholesterol and Alzheimer's disease : Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors. In: Current Drug Targets. 2004 ; Vol. 5, No. 6. pp. 517-528.
@article{278e543038294956aa694b32ce2e01b3,
title = "Cholesterol and Alzheimer's disease: Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors",
abstract = "Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (AP) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Aβ or non-amyloid proteins. However, the mechanisms of neurotoxicity of Aβ and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the E4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Aβ has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.",
keywords = "Aging, Apolipoprotein E, Cognition, Dementia, Diets, High fats, Memory, Myelin, Secretase",
author = "Kumar Sambamurti and Granholm, {Ann Charlotte} and Kindy, {Mark S.} and Bhat, {Narayan R.} and Greig, {Nigel H.} and Debomoy Lahiri and Mintzer, {Jacobo E.}",
year = "2004",
month = "8",
doi = "10.2174/1389450043345335",
language = "English",
volume = "5",
pages = "517--528",
journal = "Current Drug Targets",
issn = "1389-4501",
publisher = "Bentham Science Publishers B.V.",
number = "6",

}

TY - JOUR

T1 - Cholesterol and Alzheimer's disease

T2 - Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors

AU - Sambamurti, Kumar

AU - Granholm, Ann Charlotte

AU - Kindy, Mark S.

AU - Bhat, Narayan R.

AU - Greig, Nigel H.

AU - Lahiri, Debomoy

AU - Mintzer, Jacobo E.

PY - 2004/8

Y1 - 2004/8

N2 - Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (AP) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Aβ or non-amyloid proteins. However, the mechanisms of neurotoxicity of Aβ and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the E4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Aβ has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

AB - Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (AP) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Aβ precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Aβ deposition. Several biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which Aβ is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Aβ or non-amyloid proteins. However, the mechanisms of neurotoxicity of Aβ and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the E4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Aβ has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors.

KW - Aging

KW - Apolipoprotein E

KW - Cognition

KW - Dementia

KW - Diets

KW - High fats

KW - Memory

KW - Myelin

KW - Secretase

UR - http://www.scopus.com/inward/record.url?scp=3442878151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3442878151&partnerID=8YFLogxK

U2 - 10.2174/1389450043345335

DO - 10.2174/1389450043345335

M3 - Article

VL - 5

SP - 517

EP - 528

JO - Current Drug Targets

JF - Current Drug Targets

SN - 1389-4501

IS - 6

ER -