Amyloid Precursor Protein and Ferritin Translation: Implications for Metals and Alzheimer's Disease Therapeutics

Abstract

Iron was shown to closely regulate the expression Alzheimer's Amyloid Precursor Protein (APP) gene at the level of message translation. Intracellular levels of APP holoprotein were shown to be modulated by a mechanism that is similar to the pathway by which iron controls the translation of the ferritin L- and H mRNAs by Iron-responsive Elements in their 5'untranslated regions (5'UTRs)[48]. More recently APP gene transcription was found to be responsive to copper deficit where the Menkes protein depleted fibroblasts of copper, an event that suppressed transcription of APP through metal regulatory and copper regulatory sequences upstream of the 5' cap site [1]. Genetic and biochemical evidence has also linked the biology of metals (Fe, Cu and Zn) to Alzheimer's disease. The genetic discovery that alleles in the hemochromatosis gene accelerate the onset of disease by five years [2] has certainly validated interest in the model wherein metals (iron) accelerate the course of AD. Biochemical measurements demonstrated elevated levels of copper zinc and iron in the brains of AD patients [3]. Current models have to account for the fact that the Aβ-amyloid precursor protein (APP) of Alzheimer's disease is a copper binding metalloprotein [4]. From in vitro experiments, copper zinc and iron accelerated the aggregation the Aβ peptide and enhanced metal catalyzed oxidative stress associated with amyloid plaque formation [5]. These amyloid associated events remain the central pathological hallmark of AD in the brain cortex region. The involvement of metals in the plaque of AD patients and the demonstration of metal dependent translation of APP mRNA have encouraged the development of chelators as a major new therapeutic strategy for the treatment of AD, running parallel to the development of a vaccine. We screened 1,200 FDA pre-approved drugs for lead compounds that limited APP 5'UTR directed translation of a reporter gene, and identified several chelators as lead compounds. In a cell based secondary assay we found that the APP 5'UTR directed drugs desferrioxamine (Fe 3 + chelator), tetrathiolmobdylate (Cu 2 + chelator) and dimercaptopropanol (Pb 2 + , Hg 2 + chelator) each suppressed APP holoprotein expression (and lowered Aβ peptide secretion) [6, 7]. These agents will be tested as potentially relevant anti amyloid drugs for controlling the progression of Alzheimer's disease. Our findings have practical implications for Alzheimer's disease therapy but also support the hypothesis that APP is a metalloprotein with an integral role to play in Fe, Cu and Zn metabolism.