Does the Development of Alzheimer’s Disease Start in the Prenatal Period?

Nasser H. Zawia, Ph.D.
University of Rhode Island
R21ES13022 and R01ES08104

Background: Many epidemiologic studies over the last 50-60 years have suggested that fetal under-nutrition and low birth weights are associated with adverse health conditions such as diabetes, heart failure, and stroke later in life. The fetal basis of adult disease is an hypothesis that has grown from these studies. Tissues and organs are known to go through critical stages of development which coincide with rapid growth. Conceptually, environmental exposures or nutritional deficits during these periods could lead to alterations in development via changes in gene expression or gene imprinting, which manifest as diseases or conditions later in life.

Alzheimer’s disease has been suggested as having a possible fetal basis. Studies have suggested that Alzheimer’s has an environmental component and scientists have postulated that the development of amyloid protein plaques, a hallmark of Alzheimer’s, may result from early exposure to environmental agents. However, the specific exposures and the molecular basis of such latent effects have not been characterized.

Advance: Scientists at the University of Rhode Island exposed laboratory rats to lead and monitored the expression of beta-amyloid precursor protein (APP) throughout their lives. Snippets of APP make up the amyloid plaques that inhibit proper neural function in people with Alzheimer’s disease. They also measured a transcription factor that regulates expression of APP known as Sp1. They found that rats exposed to lead early in life had a transient increase in APP gene expression at the time of exposure followed by over-expression 20 months after the lead exposure period had ended. The activity of Sp1 and APP and beta amyloid protein levels were also increased at the late stage of life. However, older rats given similar doses of lead did not exhibit increases in gene expression, Sp1 activity, or protein levels.

Implications: These data suggest fetal exposure to the toxic heavy metal lead results in increased APP gene expression leading to increases in beta amyloid plaque formation at late stages of life even without life-time exposure. The study leads to the conclusion that lead permanently interfered with the programmed regulation of the APP gene established during development and may cause or influence neurodegenerative changes later in life.

Citation: Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci. 2005 Jan 26;25(4):823-9.