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Alzheimer’s disease (AD) is a neurodegenerative disease that is responsible for up to 80% of all dementia cases. Hallmarks of AD include the presence of beta-amyloid (Aβ) deposits and twisted strands of abnormal hyperphosphorylated tau forming neurofibrillary tangles (NFTs), which ultimately lead to damage and death of nerve cells in the brain. Symptoms of the disease include impairments in cognitive and functional abilities that gradually worsen as the disease progress. Finally, in advanced AD, patients become unable to perform basic daily activities, become more susceptible to infections, and ultimately die. Only five drugs are FDA-approved for use in AD, which only provide temporary symptomatic relief without capabilities of modifying the progression of the disease. Tolfenamic acid is a non-steroidal antiinflammatory drug that has the potential for slowing the progression of AD by inducing the degradation of the transcription factor specificity protein 1 (Sp1). Sp1 regulates the expression of several AD-related genes including amyloid precursor protein (APP), tau and beta-site APP-cleaving enzyme 1 (BACE1). To investigate the ability of tolfenamic acid to cross the blood brain barrier (BBB), multiple approaches were utilized. In silico computational models to predict logBB and logPS for CNS penetration indicated that tolfenamic acid could transfer passively through the BBB. In addition, immobilized artificial membrane (IAM) chromatography using a phosphatidylcholine column was utilized for the in vitro determination of the brain penetration capacity factor [(KIAM/MW )x10] of tolfenamic acid. The results showed that the [(KIAM/MW )x10] for tolfenamic acid was 2.73 indicating its ability to cross the BBB and penetrate into the brain. Upon intravenous (IV) administration of tolfenamic acid to guinea pigs and mice, LC-MS analysis revealed the presence of tolfenamic acid in the extracted brain tissue. This in vivo approach was also used to estimate the brain-to-plasma ratio (Kp) for tolfenamic acid, which was 0.11. Thus, using in silico, in vitro and in vivo methods, we confirmed the ability of tolfenamic acid to cross the BBB. The study offers a guide of using multiple approaches to predict the ability of different compounds to penetrate the

Brain Penetration of Tolfenamic Acid and its Ability to Enhance the Cognitive Functions and to Lower Amyloid Pathology in Animal Models of Alzheimer's Disease