Four million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market driving value of this therapeutic class to over US$1.2 billion in 2001. Although current AD treatments center on treating symptoms, future strategies are more likely to modify the course of the disease. The most widely accepted hypothesis on the etiopathogenesis of AD proposes that aggregates of the amyloid protein, trigger tau hyperphosphorylation and neural degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation.

The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. The focus of retinoid attention has been skin conditions and cancer, however although efficacy has been demonstrated in acute promyelocytic leukemia and various skin cancers, the extension of therapeutic benefit to other diseases has been limited. In our recent dossier "Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" (click here for access) we set out to offer a full and up to date insight into the complexities of the retinoids. Furthermore we describe how these complexities relate to the limited therapeutic potential of the retinoids and strategies for overcoming these limitations.

As our understanding of the retinoids increases so do their therapeutic indications. For example COPD and obesity have both recently emerged as targets for retinoic acid receptor ligands. Most recently Boston based researchers have put forward the hypothesis that late onset AD is influenced by the availability in brain of retinoic acid. This hypothesis is based on a body of genetic, metabolic, and environmental/dietary evidence. For example, significant genetic linkages to AD are demonstrated for markers close to four of the six retinoic acid receptors; three of the four retinol-binding proteins and the retinoic acid-degrading cytochrome P450 enzymes (for further information on each of these proteins and retinoid pathways go to our retinoid dossier). Retinaldehyde dehydrogenase (RLDH), the enzyme that forms retinoic acid from retinaldehyde, was present in hippocampus, frontal cortex, and parietal cortex, and its activity in the hippocampus and parietal cortex of Alzheimer diseased brains was 1.5- to 2-fold higher compared to controls. In contrast, the RLDH activity of frontal cortex was the same for both Alzheimer diseased and control groups.

Retinoid responsive transgenes have been shown to be highly active in the hippocampus and the activation of such genes has been reported to facilitate neurotrophin-induced maturation of stem cells into neurons. While retinoic acid may be important in neurogenesis, defects in the retinoid pathway may lead to impaired neurological function. This is supported by data showing that retinoid receptor expression is reduced in aged mice and that this is related to behavioral deficits consistent with diminished cognitive function. This could be reversed by retinoic acid treatment. This and the genetic/molecular evidence linking the retinoids to Alzheimer’s disease suggests that retinoic acid or its mimics may represent a useful approach to the treatment of cognitive disorders. Of particular interest to the treatment of Alzheimer’s disease it has been shown that the reductions in acetylcholine content caused by Abeta42 could be prevented by a co-treatment with retinoic acid.

On the other hand however, evidence is also available to suggest that retinoic acid can increase secreted Abeta40 and Abeta42. Of interest the response was biased towards the latter, more cytotoxic form of beta amyloid. Careful drug design could therefore conceivably lead to the development of a treatment that both improves cognition and also limits the suggested underlying cause of Alzheimer’s disease.

With the advent of improved models of Alzheimer's disease as well as a greater inventory of pharmacological tools able to probe retinoid biology, further studies designed to probe this provocative link between the retinoids and AD are eagerly awaited.

Entry date March, 2003

Adapted from Goodman & Pardee, Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2901-5 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk