ot: Lead Link To Alzheimer's Disease? environment, epigenetics, amyloidogenesis

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*Lead Link To Alzheimer's Disease?*

Early Lead Poisoning May Boost Alzheimer's Brain Chemicals Years Later,

Lab Tests Show

Jan 2, 2008

http://www.cbsnews.com/stories/2008/01/02/health/webmd/main3668022.shtml

(WebMD) Lead poisoning in infancy may make Alzheimer's disease more

likely decades later, a new study shows.

Lead poisoning is a well-known danger, especially for young children.

Months or years of lead poisoning can stunt children's growth and damage

their brain, kidneys, hearing, and mental development.

Early lead poisoning may also tinker with genes in a way that sets the

stage for Alzheimer's disease as an adult, according to the new study,

which is based on monkeys, not people.

The study included two groups of baby monkeys that drank formula for the

first 400 days of their life. One group of monkeys got ordinary,

lead-free formula. The scientists added low levels of lead to the other

group's formula.

No health problems were seen in the monkeys during the 23-year study.

The scientists checked the monkey's brains at the end of the study. The

monkeys that drank the lead-laced formula as babies had higher levels of

Alzheimer's-related proteins and more DNA damage than the other monkeys.

Lead poisoning in infancy may have made the monkeys' genes make more of

the Alzheimer's-related proteins years later, according to the

researchers, who included the University of Rhode Island's Nasser Zawia,

PhD.

Their findings appear in The Journal of Neuroscience.

By Miranda Hitti

Reviewed by Louise Chang

©2008 WebMD, Inc. All rights reserved.

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1: J Mol Neurosci. 2008;34(1):1-7. Epub 2007 Apr 17.Links

*The environment, epigenetics and amyloidogenesis*.

Wu J, Basha MR, Zawia NH.

Department of Biomedical and Pharmaceutical Sciences, University of

Rhode Island, Kingston, RI, 02881, USA, nzawia@....

Alzheimer's Disease (AD) is a progressive, irreversible

neurodegenerative disease. Despite several genetic mutations (Haass et

al., J. Biol. Chem. 269:17741-17748, 1994; Ancolio et al., Proc. Natl.

Acad. Sci. USA 96:4119-4124, 1999; Munoz and Feldman, CMAJ 162:65-72,

2000; Gatz et al., Neurobiol. Aging 26:439-447, 2005) found in AD

patients, more than 90% of AD cases are sporadic (Bertram and Tanzi,

Hum. Mol. Genet. 13:R135-R141, 2004). Therefore, it is plausible that

environmental exposure may be an etiologic factor in the pathogenesis of

AD. The AD brain is characterized by extracellular beta-amyloid (Abeta)

deposition and intracellular hyperphosphorylated tau protein. Our lab

has demonstrated that developmental exposure of rodents to the heavy

metal lead (Pb) increases APP (amyloid precursor protein) and Abeta

production later in the aging brain (Basha et al., J. Neurosci.

25:823-829, 2005a). We also found elevations in the oxidative marker

8-oxo-dG in older animals that had been developmentally exposed to Pb

(Bolin et al., FASEB J. 20:788-790, 2006) as well as promotion of

amyloidogenic histopathology in primates. These findings indicate that

early life experiences contribute to amyloidogenesis in old age perhaps

through epigenetic pathways. Here we explore the role of epigenetics as

the underlying mechanism that mediates this early exposure-latent

pathogenesis with a special emphasis on alterations in the methylation

profiles of CpG dinucleotides in the promoters of genes and their

influence on both gene transcription and oxidative DNA damage.

PMID: 18157652

2: free online:

http://www.jneurosci.org/cgi/content/full/25/4/823

J Neurosci. 2005 Jan 26;25(4):823-9.

*The fetal basis of amyloidogenesis*: exposure to lead and latent

overexpression of amyloid precursor protein and beta-amyloid in the

aging brain.

Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK,

Zawia NH.

Department of Biomedical and Pharmaceutical Sciences, University of

Rhode Island, Kingston, Rhode Island 02881, USA.

The fetal basis of adult disease (FeBAD) hypothesis states that many

adult diseases have a fetal origin. According to FeBAD, injury or

environmental influences occurring at critical periods of organ

development could result in " programmatic " changes via alterations in

gene expression or gene imprinting that may result in functional

deficits that become apparent later in life. Alzheimer's disease (AD) is

a progressive neurodegenerative disorder that is characterized by

excessive deposits of aggregated beta-amyloid (Abeta) peptides, which

are snippets of the beta-amyloid precursor protein (APP). The

predominantly sporadic nature of AD suggests that the environment must

play a role in neurodegeneration. To examine latent responses to an

environmental agent, we exposed rodents to lead and monitored the

lifetime expression of the APP gene. We observed that APP mRNA

expression was transiently induced in neonates, but exhibited a delayed

overexpression 20 months after exposure to Pb had ceased. This

upregulation in APP mRNA expression was commensurate with a rise in

activity of the transcription factor Sp1, one of the regulators of the

APP gene. Furthermore, the increase in APP gene expression in old age

was accompanied by an elevation in APP and its amyloidogenic Abeta

product. In contrast, APP expression, Sp1 activity, as well as APP and

Abeta protein levels were unresponsive to Pb exposure during old age.

These data suggested that environmental influences occurring during

brain development predetermined the expression and regulation of APP

later in life, potentially altering the course of amyloidogenesis.

PMID: 15673661

3. *http://tinyurl.com/38h92m*

*Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile

Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental

Origin and Environmental Link for AD*

The Journal of Neuroscience, January 2, 2008, 28(1):3-9;

doi:10.1523/JNEUROSCI.4405-07.2008

Jinfang Wu,1 Md. Riyaz Basha,1 Brock,1 P. ,2

Cardozo-Pelaez,2 A. McPherson,3 Harry,3 Deborah C.

Rice,4 Maloney,5 Demao Chen,5 Debomoy K. Lahiri,5 and Nasser H. Zawia1

1Department of Biomedical and Pharmaceutical Sciences, University of

Rhode Island, Kingston, Rhode Island 02881, 2Department of Biomedical

and Pharmaceutical Sciences, Center for Environmental Health Sciences,

University of Montana, Missoula, Montana 59812, 3National Institutes of

Health, Research Triangle Park, North Carolina 27709, 4Maine Department

of Health and Human Services, Augusta, Maine 04333, and 5Laboratory for

Molecular Neurogenetics, Institute for Psychiatric Research, Department

of Psychiatry, Indiana University School of Medicine, Indianapolis,

Indiana 46202

Correspondence should be addressed to Dr. Nasser H. Zawia, Department of

Biomedical and Pharmaceutical Sciences, University of Rhode Island,

Kingston, RI 02881. Email: nzawia{at}uri.edu

The sporadic nature of Alzheimer's disease (AD) argues for an

environmental link that may drive AD pathogenesis; however, the

triggering factors and the period of their action are unknown. Recent

studies in rodents have shown that exposure to lead (Pb) during brain

development predetermined the expression and regulation of the amyloid

precursor protein (APP) and its amyloidogenic ?-amyloid (A?) product in

old age. Here, we report that the expression of AD-related genes [APP,

BACE1 (?-site APP cleaving enzyme 1)] as well as their transcriptional

regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to

Pb as infants. Furthermore, developmental exposure to Pb altered the

levels, characteristics, and intracellular distribution of A? staining

and amyloid plaques in the frontal association cortex. These latent

effects were accompanied by a decrease in DNA methyltransferase activity

and higher levels of oxidative damage to DNA, indicating that epigenetic

imprinting in early life influenced the expression of AD-related genes

and promoted DNA damage and pathogenesis. These data suggest that AD

pathogenesis is influenced by early life exposures and argue for both an

environmental trigger and a developmental origin of AD.