COMMENTARY Proton pump inhibitors: predisposers to Alzheimer disease? M. K. Fallahzadeh*, A. Borhani Haghighi  MD and M. R. Namazi à MD *Autoimmune Diseases Research Center,  Comparative Medicine Research Center ⁄ Department of Neurology and àMedicinal and Natural Chemistry Products Research Center and Department of Dermatology, Shiraz University of Medical Sciences, Shiraz, Iran SUMMARY The abnormal processing of amyloid-b peptide (Ab) and resultant formation of fibrillar Ab (fAb) are major events in the pathogenesis of Alzhei- mer disease (AD). Microglia as the phagocytic cells of the brain can engulf and digest fAb within their acidic lysosomes. The lysosomes of AD patients are less acidic and therefore less capable of clearance of fAb. Vacuolar proton pumps (V-ATPases) which are found abundantly in microglia and macrophages, acidify lysosomes by pumping protons into these structures. Proton pump inhibitors (PPIs) can inhibit V-ATPases of the lysosomes. These drugs are shown to pene- trate the blood–brain barrier in animals. PPIs are consumed for long periods in conditions such as gastroesophageal reflux disease, with the resul- tant exposure of the human brain to the sub- stantial amounts of PPIs. We hypothesize that by blocking the V-ATPases on microglial lysosomes, PPIs may basify lysosomes and hamper degra- dation of fAb. Chronic consumption of PPIs may thus be a risk factor for AD. Keywords: amyloid beta, lysosomes, microglia, vacuolar proton pumps Alzheimer disease (AD) is the most common form of dementia (1). The abnormal processing of amy- loid-b peptide (Ab) plays a pivotal role in the pathogenesis of AD (2). When amyloid precursor proteins (APP) are cleaved by specific secretases, the endproduct is Ab (1). Ab aggregation leads to formation of fibrillar b-pleated sheet structures that are major components of extracellular senile plaques which are found in the brains of AD patients (3). This process is accelerated either by excessive APP production or via mutations at the beta-secretase or gamma-secretase site (1, 3). Treatment modalities that lead to clearance of fibrillar Alzheimer amyloid-b peptide (fAb) have been demonstrated to be effective in treatment of murine models of AD (3). Microglia which represent the mononuclear phagocytic system of the brain can play an impor- tant role in the pathogenesis of AD (3). These cells engulf fAb and digest it with their lysosomal pro- teases (3). Lysosomal proteases need an acidic environment for optimal function (3). It is shown that the lysosomes of the microglia in AD patients are less acidic than their normal counterparts and are therefore less capable of clearance of fAb (3). Stimulation of microglia by proinflammatory cyto- kines, IL-6 and macrophage colony stimulating fac- tor, results in differentiation of microglia into the activated cells that resemble macrophages in the expression of various cell surface proteins as well as acidification of lysosomal environment (3). This stimulation enhances fAb clearance by microglia (3). The regulation of lysosomal pH is a complex process (3). Among the factors that can reduce lysosomal pH are the vacuolar proton pumps (V-ATPases) which pump protons from the cyto- plasm to the lumen of vacuoles or into the extra- cellular space using the energy produced by ATP hydrolysis (4). The B and E subunits of the V-ATPases have been demonstrated to be expres- sed abundantly in microglia and macrophages and contribute to the acidification of the lysosomes in these cells (3). Proton pump inhibitors (PPIs) are the first choice drugs for treating acid-related diseases (4). These Received 25 March 2009, Accepted 30 April 2009 Correspondence: M. R. Namazi, Department of Dermatology, Faghihi Hospital, Shiraz, Iran. Tel. ⁄ fax: +98 7112 300 049; e-mail: namzi_mr@yahoo.com Journal of Clinical Pharmacy and Therapeutics (2010) 35, 125–126 doi:10.1111/j.1365-2710.2009.01100.x Ó 2009 Blackwell Publishing Ltd 125