Four million Americans currently suffer from Alzheimer's disease and experts estimate that by 2025 22 million people around the world will be afflicted. Alzheimer's disease patients suffer both affective and memory disorders and current treatments generally focus on the use of antidepressants and memory enhancers to treat these symptoms. In a recent DiscoveryDossier we analyze the involvement of the brain renin-angiotensin system in mood and cognition and suggest that angiotensin receptor ligands may be of therapeutic benefit in patients suffering from Alzheimer’s disease and/or depression . As an alternative to treating disease symptoms recent therapeutic developments include the targeting of beta amyloid, fibrillogenesis of which is responsible for triggering a cascade of physiological events that contribute directly to the initiation and progression of Alzheimer's disease. The exact reason for the neurotoxic effects of beta amyloid is unclear but altered calcium regulation, immune stimulation and/or mitochondrial damage have all been proposed as causative factors. Whatever the cause of neurotoxicity, beta-amyloid is responsible for both affective and memory disorders and blocking these detrimental affects of beta-amyloid is expected to be of clinical benefit. Vaccine approaches to the lowering of amyloid levels are highlighted in the “Focus on CNS disease” section of this edition of TherapeuticAdvances; here we feature a novel strategy for countering amyloid mediated changes in mood. Recent data emerging from INSERM support an antidepressant efficacy of the selective sigma(1) receptor agonists igmesine or PRE-084 in mice subjected to icv administration of beta(25-35)-amyloid peptide. The sigma(1) agonists igmesine and PRE-084 showed an enhanced antidepressant efficacy in beta(25-35) amyloid peptide treated animals, contrary to the classical antidepressants fluoxetine and desipramine. The beta(25-35) amyloid treated animals exhibited decreased progesterone levels in the hippocampus. The behavioral efficacy of sigma(1) agonists is known to depend on neuro(active)steroids levels synthesized by glial cells and neurones, which are affected by the beta-amyloid toxicity. Historic data suggested that sigma site numbers are decreased in CA1 area of the anterior hippocampus in patients, but sigma subtypes were not discriminated and little data is currently available concerning sigma(1) receptors. The present behavioral study suggests that sigma(1) agonists, due to their selective efficacy in amyloid induced mood disorders, may alleviate the depressive symptoms associated with Alzheimer's disease by interacting with pathophysiological pathways rather than by an anti-depressant effect per se. Few sigma agonists are currently in development and this data therefore suggests a novel and effective approach to Alzheimer's disease.

January, 2003

Adapted from Urani et al, Behav Brain Res 2002 Aug 21;134(1-2):239-47

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