The decrease of brain estrogen was considered to be closely involved in Alzheimer's disease in women. Moreover, less estrogen receptor β (ERβ) was detected in mitochondrial, nuclear, and cytosolic fractions of female AD brains. The level of brain ERβ in aged rats is also decreased significantly. ERβ depletion impairs learning and memory of mice, while estrogen or ERβ selective agonist could activate the expression of synapse related proteins. ERβ colocalizes with mitochondria in primary neuron, suggesting that ERβ might play roles in regulating mitochondrial function and affect the function of neuron accordingly.