A connection has been established between Alzheimer's disease and diabetes during the past decade, as insulin resistance, which is a characteristic hallmark of diabetes, has also been observed in brains of subjects suffering from Alzheimer's disease.[57] Neurotoxic oligomeric amyloid-β species decrease the expression of insulin receptors on the neuronal cell surface[58] and abolish neuronal insulin signaling.[57] It has been suggested that neuronal gangliosides, which take part in the formation of membrane lipid microdomains, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface.[59] In Alzheimer's disease, oligomeric amyloid-β species trigger TNF-α signaling.[57] c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling.[57][60][61] The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.[62][63]