Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical manifestations appearing in old age, however, the initial stages of this disease may begin early in life. AD is characterized by the presence of excessive deposits of aggregated beta-amyloid (Abeta) peptides, which are derived from the beta-amyloid precursor protein (APP) following processing by beta-secretase and gamma-secretase. Recently, we have reported that developmental exposure of rats to Pb resulted in latent elevation of APP mRNA, APP, and Abeta in old age. Here we examined whether latent up-regulation in APP expression and Abeta levels is exacerbated by concurrent disturbances in APP processing or Abeta aggregation. Among the environmental metals tested, only Abeta solutions containing Pb promoted the formation of Abeta aggregates at nanomolar concentrations. The lifetime profiles of alpha-, beta-, and gamma-secretases remained constant in adult and aging animals, and developmental exposure to Pb did not alter them. Furthermore, the addition of various concentrations of Pb (0.1 to 50 microM) to cerebral cortical extracts derived from control animals also did not affect the proteolytic activities of these enzymes. 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 Abeta aggregation in old age. In rodents, these events occur without Pb-induced disturbances to the enzymatic processing of APP. The aforementioned results provide further evidence for the developmental basis of amyloidogenesis and late-life disturbances in AD-associated proteins by environmental agents.