The main objective of this proposal is to demonstrate that the protective effects of a Chinese herbal extract called tetramethylpyrazine (TMP) in an Alzheimer¡¯s disease (AD) mouse model. TMP is an active ingredient in the Chinese herbal medicine called chuanxiong and has been commonly used in the clinic for treatment of cardiovascular diseases in China. Previous studies have demonstrated strong neuroprotective effects of TMP. Oral administration or injection of TMP protected neuronal cells against ischemic or traumatic brain or spinal cord injury and promoted functional recovery in rodents and rabbit. Importantly, our preliminary studies demonstrate that TMP can significantly improve learning and memory performance of an Alzheimer¡¯s transgenic mouse and related brain pathology. Surprisingly, TMP have not yet been carefully evaluated in AD. We therefore propose a proof-of-concept study to test the hypothesis that oral administration of TMP will attenuate neuropathological changes and improve cognitive deficits in a well-studied Alzheimer¡¯s mouse model, 3xTg-AD mouse. The following Specific Aims will be tested: 1 To evaluate the effects of TMP on development of Alzheimer's pathology in AD mouse brains; 2 To evaluate the effects of TMP on the development of early cognitive deficits in AD mice; 3 To evaluate whether TMP can reverse the pathological and cognitive abnormalities in AD mice once they are established. Both age-matched normal and Alzheimer¡¯s mice (3-month old for Aims 1 & 2; 12-month old for Aim 3) will continuously receive TMP mixed with diet through mouth (300mg/Kg diet) for either 3, 6 or 9 months. The nutrients-matched diet will be used as control. Brain pathology including loss of brain cells as well as other related biochemical and pathological markers will be examined. Spatial learning will be also evaluated in some of the treated mice before sacrifice using the methods for behavioral analyses. The study aims to develop a novel approach to AD therapy that can be readily translated to the clinical setting.