Alpha-endosulfine has the ability to block ATP-sensitive potassium (K(ATP)) channels and stimulate insulin release in beta cells like sulfonylurea. Alpha-endosulfine is expressed in a wide range of tissue, including brain and endocrine tissues. Although K(ATP) channels are also present in brain and its regulators have been reported to be involved in the release of neurotransmitters such as acetylcholine that plays an important role in cognitive function, the neurobiological role of alpha-endosulfine has not been studied yet. We examined the expression levels of alpha-endosulfine protein in frontal cortex and cerebellum from patients with Down syndrome (DS) showing Alzheimer's disease (AD) pathology using Western blotting. In frontal cortex, alpha-endosulfine was detected in all of 10 controls, but only 1 (from female) out of 8 DS with weak density. In cerebellum, alpha-endosulfine was also detected in all of 9 controls, but only 1 (from male) out of 6 DS with weak density. The considerably decreased alpha-endosulfine could result in the continuous opening of K(ATP) channels and the subsequent decrease of neurotransmitters release associated with cognition. This study is of significance providing evidence for a biological role of alpha-endosulfine in brain and alpha-endosulfine protein could be a pharmacological target for therapeutic intervention.