Lead (Pb) exposure and its effect on APP proteolysis and Aβ aggregation

Abstract

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.05-4375fje; doi: 10.1096/fj.05-4375fje SPECIFIC AIMSAlzheimer's disease (AD) is characterized by excessive deposition of aggregated ␤-amyloid (A␤) peptide of 40-42 residue, which is derived from the amyloid precursor protein (APP) following processing by ␤-secretase and ␥-secretase. We have reported that developmental exposure to Pb up-regulates the expression levels of APP and its amyloidogenic A␤ 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 A␤ levels are exacerbated by concurrent disturbances in APP processing or A␤ aggregation. PRINCIPAL FINDINGS Nanomolar levels of Pb promote A␤ aggregationIncreased 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 A␤ 1-40 and A␤ 1-42 . Environmental agents could exacerbate such a situation by directly promoting A␤ aggregation; therefore, we decided to examine the effects of xenobiotic metals on human A␤ 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 A␤ and A␤ aggregates in the absence and presence of metals at various concentrations. Bis-ANS is known to bind aggregated but not monomeric A␤. The non-amyloidogenic A␤ 40-1 was used as a control in these experiments. Among the environmental metals tested, only A␤ solutions containing Pb were observed to bind tightly to bis-ANS, consistent with the presence of A␤ aggregates. The aggrega-

Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice

“…While these results may help illuminate regulation of these genes in mouse, we have previously published in greater detail on developmental expression of such genes in rodents [26, 52, 53]. …”

DNA Methylation and Alzheimer’s Disease

“…Furthermore, Lahiri et al (2007) have proposed a "Latent Early-Life Associated Regulation" (LEARn) model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents (e.g., heavy metals) (Basha et al 2005), intrinsic factors (e.g., cytokines), and dietary factors (e.g., cholesterol) (Hartmann et al 2007) perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have significant pathological results until later in life. Thus, such actions would perturb APP gene regulation at a very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Aβ deposition.…”

Genistein protects against Aβ25–35 induced apoptosis of PC12 cells through JNK signaling and modulation of Bcl-2 family messengers

“…As such, Aβ 25–35 promotes to the development of Alzheimer’s disease (AD) pathology and the resultant clinical symptoms [1, 2]. Deposition of Aβ 25–35 in brain triggers tau protein phosphorylation and formation of intracellular neurofibrillary tangles (NFT), subsequently leading to mitochondrial dysfunction and membrane rupture, which then proceeds to necrosis or apoptosis [3].…”