Metal and inflammatory targets for Alzheimer's disease

Jack T. Rogers, Debomoy Lahiri

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Alzheimer's disease (AD) has become linked to inflammation and metal biology. Metals (copper. zinc and iron) and inflamamatory 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 Aβ 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 Aβ peptide from activating microglia, the use of cytokine suppressive anti-inflammatory drugs (CSAIDS), and the continued search for a vaccine directed to Aβ sub-fragments (even though the full-length Aβ 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.

Original languageEnglish
Pages (from-to)535-551
Number of pages17
JournalCurrent Drug Targets
Volume5
Issue number6
DOIs
StatePublished - Aug 2004

Fingerprint

Alzheimer Disease
Metals
Pharmaceutical Preparations
Iron
Amyloid
Encephalitis
Chelating Agents
Inflammation
Zinc
Copper
Anti-Inflammatory Agents
Vaccines
Assays
Brain
Genes
Cytokines
Peptides
Drug therapy
Hemochromatosis
Amyloid beta-Protein Precursor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

Cite this

Metal and inflammatory targets for Alzheimer's disease. / Rogers, Jack T.; Lahiri, Debomoy.

In: Current Drug Targets, Vol. 5, No. 6, 08.2004, p. 535-551.

Research output: Contribution to journalArticle

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