How and when environmental agents and dietary factors affect the course of Alzheimer's disease

The "LEARn" model (Latent Early-Life Associated Regulation) may explain the triggering of AD

Debomoy Lahiri, Bryan Maloney, Md Riyaz Basha, Wen Ge Yuan, Nasser H. Zawia

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, τ tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are "protein-only", they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur "late in the game". Development and progression of AD has not been explained by protein-only models. In view of this limitation, we propose a "Latent Early-Life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition. This model operates on the regulatory region (promoter) of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.

Original languageEnglish
Pages (from-to)219-228
Number of pages10
JournalCurrent Alzheimer Research
Volume4
Issue number2
DOIs
StatePublished - Apr 2007

Fingerprint

Alzheimer Disease
Genes
Disease Attributes
Proteins
Intrinsic Factor
CpG Islands
Guanosine
Nucleic Acid Regulatory Sequences
Amyloid Plaques
DNA Methylation
Heavy Metals
Epigenomics
Toxicology
Methylation
Dementia
Carrier Proteins
Cell Death
Metals
Cholesterol
Cytokines

Keywords

  • Aging
  • Cholesterol
  • Dementia
  • Development
  • Diet
  • Epigenetics
  • Gene regulation
  • LEARn
  • Metal
  • Methylation
  • Promoter
  • Psychiatric disorders
  • Risk factors

ASJC Scopus subject areas

  • Biological Psychiatry
  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

How and when environmental agents and dietary factors affect the course of Alzheimer's disease : The "LEARn" model (Latent Early-Life Associated Regulation) may explain the triggering of AD. / Lahiri, Debomoy; Maloney, Bryan; Basha, Md Riyaz; Yuan, Wen Ge; Zawia, Nasser H.

In: Current Alzheimer Research, Vol. 4, No. 2, 04.2007, p. 219-228.

Research output: Contribution to journalArticle

@article{edc5ad74db3f4581a29c825d6c411945,
title = "How and when environmental agents and dietary factors affect the course of Alzheimer's disease: The {"}LEARn{"} model (Latent Early-Life Associated Regulation) may explain the triggering of AD",
abstract = "Alzheimer's disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, τ tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are {"}protein-only{"}, they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur {"}late in the game{"}. Development and progression of AD has not been explained by protein-only models. In view of this limitation, we propose a {"}Latent Early-Life Associated Regulation{"} (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition. This model operates on the regulatory region (promoter) of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.",
keywords = "Aging, Cholesterol, Dementia, Development, Diet, Epigenetics, Gene regulation, LEARn, Metal, Methylation, Promoter, Psychiatric disorders, Risk factors",
author = "Debomoy Lahiri and Bryan Maloney and Basha, {Md Riyaz} and Yuan, {Wen Ge} and Zawia, {Nasser H.}",
year = "2007",
month = "4",
doi = "10.2174/156720507780362164",
language = "English",
volume = "4",
pages = "219--228",
journal = "Current Alzheimer Research",
issn = "1567-2050",
publisher = "Bentham Science Publishers B.V.",
number = "2",

}

TY - JOUR

T1 - How and when environmental agents and dietary factors affect the course of Alzheimer's disease

T2 - The "LEARn" model (Latent Early-Life Associated Regulation) may explain the triggering of AD

AU - Lahiri, Debomoy

AU - Maloney, Bryan

AU - Basha, Md Riyaz

AU - Yuan, Wen Ge

AU - Zawia, Nasser H.

PY - 2007/4

Y1 - 2007/4

N2 - Alzheimer's disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, τ tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are "protein-only", they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur "late in the game". Development and progression of AD has not been explained by protein-only models. In view of this limitation, we propose a "Latent Early-Life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition. This model operates on the regulatory region (promoter) of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.

AB - Alzheimer's disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, τ tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are "protein-only", they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur "late in the game". Development and progression of AD has not been explained by protein-only models. In view of this limitation, we propose a "Latent Early-Life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition. This model operates on the regulatory region (promoter) of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders.

KW - Aging

KW - Cholesterol

KW - Dementia

KW - Development

KW - Diet

KW - Epigenetics

KW - Gene regulation

KW - LEARn

KW - Metal

KW - Methylation

KW - Promoter

KW - Psychiatric disorders

KW - Risk factors

UR - http://www.scopus.com/inward/record.url?scp=33846983823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846983823&partnerID=8YFLogxK

U2 - 10.2174/156720507780362164

DO - 10.2174/156720507780362164

M3 - Article

VL - 4

SP - 219

EP - 228

JO - Current Alzheimer Research

JF - Current Alzheimer Research

SN - 1567-2050

IS - 2

ER -