Therapeutic Targeting of the Endoplasmic Reticulum in Alzheimers Disease

Wayne      Chadwick; Nicholas      Mitchell; Bronwen      Martin; Stuart      Maudsley

Abstract

The extensive prevalence of Alzheimers disease (AD) places a tremendous burden physiologically, socially and economically upon those directly suffering and those caring for sufferers themselves. Considering the steady increases in numbers of patients diagnosed with Alzheimers, the number of effective pharmacotherapeutic strategies to tackle the disease is still relatively few. As with many other neurodegenerative mechanisms, AD, is characterized by the continued presence and accumulation of cytotoxic protein aggregates, i.e. of beta-amyloid and the microtubule associated protein, tau. Therefore, one novel therapeutic avenue for the treatment of AD may be the actual targeting of factors that control protein synthesis, packaging and degradation. One of the prime cellular targets that, if effectively modulated, could accomplish this is the endoplasmic reticulum (ER). The ER can not only control cellular protein synthesis, trafficking and degradation but it is also closely associated with cytoprotective mechanisms, including calcium ion regulation and unfolded protein responses. This review will delineate some of the most important functional physiological features of the ER that, if effectively modulated, could result in beneficial amelioration or remediation of the negative cellular aspects of AD initiation and progression. While not a classical drug target, even with minimal levels of beneficial modulation, its multifactorial efficacy may amplify small effects resulting in significant therapeutic efficacy.

Keywords: endoplasmic, reticulum, Alzheimer's disease, amyloid, stress, calcium, protein synthesis, folding., lysosomal degradation, apoptosis