Metal and inflammatory targets for Alzheimer's disease

Alzheimer's disease (AD) has become linked to inflammation and metal biology. Metals (copper, zinc and iron) and inflammatory cytokines are significant factors that increase the onset of sporadic late onset forms of the dementia. The genetic discovery that alleles in the hemochromatosis gene accelerate the onset of disease by five years [1] has certainly validated interest in the metallobiology of AD as originally described by biochemical criteria [2]. Also the presence of an Iron-Responsive Element (IRE) in the 5'UTR of the Amyloid Precursor Protein transcript (APP 5'UTR) [3] provided the first molecular biological support for the current model that APP of AD is a metaloprotein. At the biochemical level, copper, zinc and iron were shown to accelerate the aggregation of the Abeta peptide and enhance metal catalyzed oxidative stress associated with amyloid plaque formation [4]. These amyloid associated events remain the central pathological hallmark of AD in the brain cortex region of AD patients. 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. The other notable pathological feature of AD discussed here is inflammation. The presence of neuro-inflammatory events during AD was supported by clinical trials wherein use of non steroidal anti-inflammatory drugs (NSAIDs) was shown to reduce the risk of developing AD. Drug targets that address inflammation include the use of small, molecules that prevent Abeta peptide from activating microglia, the use of cytokine suppressive anti-inflammatory drugs (CSAIDS), and the continued search for a vaccine directed to A sub-fragments (even though the full-length Abeta immunogen generated brain-inflammation and encephalitis in some patients). Our laboratory currently uses a transfection-based assay to screen for small molecule drugs that selectively suppress the capacity of the APP 5'UTR to confer expression to a downstream reporter gene. Based on the presence of both an Interleukin-1 (IL-1) responsive acute box domain and an IRE in the APP 5'UTR, we predict that our APP 5'UTR directed drug screens will identify both novel metal chelators and novel NSAIDS. These lead drugs are readily testable to measure APP holoprotein expression in a cell based secondary assay, and by use of an APP transgenic mouse. model to test potential beneficial effects of lead drug treatments on amyloid burden.