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EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 17, 2005 as doi:10.1096/fj.05-4375fje. |
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* Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA;
Laboratory for Molecular Neurobiology and Functional Neuroproteomics, AAB043, Integrative Biosciences Institute, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland; and
Laboratory for Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
1Correspondence: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA. E-mail.nzawia{at}uri.edu
SPECIFIC AIMS
Alzheimer’s disease (AD) is characterized by excessive deposition of aggregated ß-amyloid (Aß) peptide of 40-42 residue, which is derived from the amyloid precursor protein (APP) following processing by ß-secretase and 
-secretase. We have reported that developmental exposure to Pb up-regulates the expression levels of APP and its amyloidogenic Aß products late in life. This provided the first evidence for the developmental and environmental link for disturbances in AD-associated proteins. Our aim was to examine whether latent up-regulation in APP expression and Aß levels are exacerbated by concurrent disturbances in APP processing or Aß aggregation.
PRINCIPAL FINDINGS
1. Nanomolar levels of Pb promote Aß aggregation
Increased APP expression and/or processing are believed to accelerate AD pathogenesis in humans and animal models of AD due to the increased production of the amyloidogenic peptides Aß1-40 and Aß1-42. Environmental agents could exacerbate such a situation by directly promoting Aß aggregation; therefore, we decided to examine the effects of xenobiotic metals on human Aß aggregation in vitro.
The fluorescent dye 1,1-bis(anilino)napthaline-5,5-disulfonic acid (bis-ANS) was used to probe the conformational properties of Aß and Aß aggregates in the absence and presence of metals at various concentrations. Bis-ANS is known to bind aggregated but not monomeric Aß. The non-amyloidogenic Aß 40-1 was used as a control in these experiments. Among the environmental metals tested, only Aß solutions containing Pb were observed to bind tightly to bis-ANS, consistent with the presence of Aß aggregates. The aggregation patterns observed using this method were dose dependent.
2. Developmental exposure to Pb has no latent effect on activity of secretase enzymes
We have previously shown that exposure to Pb during development up-regulates APP expression. Here we wanted to determine whether APP processing by secretases was also affected by developmental events. We profiled the cortical activity levels of 
-, ß-, and -secretases across the life span of rodents. We found that the activities of -, ß-, and -secretases peaked during early brain development, decreased to basal levels in adulthood, and remained constant for the rest of the animals’ lives. We examined the effects of Pb exposure on the activity of each secretase using cortical tissue from three different groups: control, Pb-E (exposed to 200 ppm Pb in drinking water from birth to weaning), and Pb-L (exposed to 200 ppm Pb in drinking water from 18 to 20 months). We found that there were no significant changes in the activity levels of any of the three enzymes among these groups at 20 months of age (Fig. 2
).
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CONCLUSIONS
AD is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. Most theories and mechanisms proposed to explain the pathogenesis of sporadic AD focus on events or disturbances that occur during old age. The long latency of AD suggests that this neurodegenerative disease remains asymptomatic for decades before a progressive accumulation of damage becomes clinically detectable. Our findings suggest that the initial events which trigger this disease begin very early in life and may be worsened by re-exposure to environmental agents late in life. Therefore, we propose that amyloidogenesis is promoted by a latent response to developmental reprogramming of the expression of the APP gene by early exposure to Pb as well as enhancement of Aß aggregation in old age. In rodents, these events occur without Pb-induced disturbances to the enzymatic processing of APP. The findings described above provide further evidence for the developmental basis of amyloidogenesis and late life disturbances in AD-associated proteins by environmental agents.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4375fje;
This article has been cited by other articles:
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  S. A. Bakheet, Md. R. Basha, H. Cai, and N. H. Zawia Lead Exposure: Expression and Activity Levels of Oct-2 in the Developing Rat Brain Toxicol. Sci., February 1, 2007; 95(2): 436 - 442. [Abstract] [Full Text] [PDF]
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) show an elevation in intermediates in the pathway due to Pb exposure.