Alzheimer's disease (AD) is a progressive degenerative disease of the brain and the leading cause of dementia that affects millions of elderly people world-wide, and the advent of pre-symptomatic biomarkers has revealed that many millions more are in the process of developing AD. These numbers will climb dramatically by 2050 if no preventive treatment(s) become available. Although it cannot explain all features of AD, a scientifically well-supported theory on its pathogenesis suggests that AD is precipitated in large part by the extracellular deposition of -amyloid peptide (A), which leads to aggregation and plaque formation, and the abnormal hyperphosphorylation of tau protein, which leads to the intracellular formation of neurofibrillary tangles. AD patients experience a debilitating erosion of memory and cognition due to profound neuronal and neurotransmitter losses initiated in considerable part by A accumulation in the limbic- and neo-cortices regions of the brain. There is a strong need to develop novel medications for new therapeutic approaches for the treatment of AD. We have shown that the indirect activation of the CB1 cannabinoid receptor by inhibiting the enzyme Fatty Acid Amide Hydrolase (FAAH) has a neuroprotective effect. In this proposal, we propose to design novel druggable FAAH inhibitors with high brain permeability to generate 2-3 potent and selective compounds in preventing the synaptotoxicity induced by Aβ oligomers on hippocampal LTP, an electrophysiological correlate of learning and memory. LTP and related electrophysiological analyses have become a highly relevant readout for AD mechanisms and for screening therapeutic agents. Preliminary data with in-house FAAH inhibitors have shown to restore A impaired hippocampal LTP, a compelling finding that could translate to novel therapeutics for AD. To our knowledge, such efforts currently are not being pursued within academia or the pharmaceutical industry.