[Fwd: Fetal Basis of Amyloidogenesis: Exposure to Lead - an Alzheimer's etiology?]

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Rats exposed neonatally to low levels of lead have increased amyloid

deposits in their brains in old age, according to research on rats,

implicating early lead exposure in the causation of Alheimer's disease.

The exposure permanently alters the behavior of the APP gene, which

produces the amyloid peptide. Exposure in old age to the same lead

level, however, did not produce the effect. These results suggest

Alzheimer's may be one of an increasing number of adult diseases caused

by fetal exposures.

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

Journal of Neuroscience.

The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent

Overexpression of Amyloid Precursor Protein and -Amyloid in the Aging Brain

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The Journal of Neuroscience, January 26, 2005, 25(4):823-829;

doi:10.1523/JNEUROSCI.4335-04.2005

Full Text <http://www.jneurosci.org/cgi/content/full/25/4/823>

Full Text (PDF) <http://www.jneurosci.org/cgi/reprint/25/4/823>

M. Riyaz Basha,1 Wei Wei,1 Saleh A. Bakheet,1 Nathalie Benitez,1 Hasan

K. Siddiqi,1 Yuan-Wen Ge,2 Debomoy K. Lahiri,2 and Nasser H. Zawia1

1Department of Biomedical and Pharmaceutical Sciences, University of

Rhode Island, Kingston, Rhode Island 02881, and 2Laboratory of Molecular

Neurogenetics, Department of Psychiatry, Institute of Psychiatric

Research, Indiana University School of Medicine, Indianapolis, Indiana

46202

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 -amyloid (A) peptides, which are

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

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 A product. In contrast, APP

expression, Sp1 activity, as well as APP and A 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.

Key words: Alzheimer; -peptide; CNS; dementia; development; environment;

latency; transcription

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Received Oct 19, 2004; revised December 3, 2004; accepted December 4, 2004.