Approximately 15% of people who live to the age of 65 will develop some form of dementia; by age 85, that proportion increases to at least 35%. The most common of all the dementias is Alzheimer's disease (AD). Existing in two forms, early onset familial disease (FAD) and late onset disease. Four million Americans currently suffer from the condition, and experts estimate that 22 million people around the world will be so afflicted by 2025. Acetylcholinestase inhibitors dominate the current AD market. There are four such products marketed for mild to moderate AD, namely Cognex (tacrine), Aricept (donepezil), Exelon (rivastigmine) and Reminyl (galantamine). In total, the current AD market was worth over $1.2 billion in 2001. Although disease modifying products such as those able to prevent the accumulation or the toxicity of Aß42 (see for example our recent report "Glycogen synthase kinase-3 inhibitors: Proof of concept and therapeutic opportunities for the treatment of diabetes, Alzheimer's disease, stroke & bipolar disorder") will undoubtedly provide a massive boost to the AD market, those molecules able to effectively treat the symptoms of diseases (see for example "Angiotensin as a target for the treatment of Alzheimer's disease, anxiety and depression") will continue to dominate this market for the foreseeable future. Leptin has been receiving considerable attention from the drug development sector for a number of years now, largely in relation to its role in metabolic disease. Leptin is released into the blood from fat cells and circulates to the brain where it crosses the blood-brain barrier to act at receptors within the central nervous system. Leptin inhibits food intake, reduces body weight and stimulates energy expenditure. Leptin expression increases after food intake and decreases during fasting. Reduced expression has been shown to evoke insulin resistance, while a leptin agonist has recently been shown to not only reduce body weight and glucose levels in obese animals but also to increase insulin sensitivity. Despite the promise that leptin agonists may have for the treatment of both diabetes and obesity, such molecules have only met with limited success in clinical trials. Additional non-metabolic functions of leptin such as bone growth are rapidly emerging. Here we report on recent data suggesting that leptin may be involved in memory function. The CA1 hippocampal region of Zucker and db/db mice, neither of which express functional leptin receptors, showed impairments of long-term potentiation and long-term depression. Exogenous leptin did not reverse these impairments suggesting that leptin receptor activation plays an important role in memory function. These mice also showed impaired spatial memory in the Morris water-maze test further supporting a possible therapeutic role of leptin or its receptor agonists in the treatment of memory disorders such as AD

November, 2002

Adapted from Li et al, Neuroscience 2002;113(3):607-15

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