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.

The reduction in levels of the potentially toxic amyloid-␤ peptide (A␤) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the A␤ precursor protein (␤APP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces ␤APP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in ␤APP processing. Phenserine treatment resulted in decreased secretion of soluble ␤APP and A␤ into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of ␤APP protein expression by phenserine was posttranscriptional as it suppressed ␤APP protein expression without altering ␤APP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5-mRNA leader sequence of ␤APP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces A␤ levels by regulating ␤APP translation via the recently described iron regulatory element in the 5-untranslated region of ␤APP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of ␤APP expression that can result in a substantial reduction in the level of A␤. T he major pathological hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative condition leading to loss of memory, are characterized by the appearance of senile plaques that are primarily composed of A␤ and neurofibrillary tangle aggregates (1, 2). A␤, a 40-to 42-residue peptide, is derived from a larger protein, ␤APP (695-770 residues) whose biological functions remain to be fully determined but whose pathological role may be separated on the basis of its final proteolyzed form (1, 3). ␤APP derivatives are generated by three enzymatic activities termed ␣-, ␤-, and ␥-secretases to produce different protein fragments that are either neuroprotective or amyloidogenic. Recently, four groups have identified an aspartyl protease with ␤-secretase-like properties (4-7) that may serve as a therapeutic marker. However, its value as a target for drug development is complicated by its location within two (plasma and Golgi) membranes. Furthermore, the role of alternative compensatory activities remains unclear. Indeed, a second enzyme, Thimet oligopeptidase, was found capable of ␤-secretase activity in transfected COS cells (8). A major pharmaceutical industry focus has been to look for agents that reduce amyloidogenic processing using compounds that can manipulate ␤APP to produce nonamyloidogenic by-products. However, it is important...