The role of the endoplasmic reticulum in the accumulation of p-amyloid peptide in Alzheimer's disease

Increased cerebral levels of A beta(42) peptide, either as soluble or aggregated forms, are suggested to play a key role in the pathogenesis of Alzheimer's disease (AD). The identification of genetic defects in presenilins and beta-amyloid precursor protein (beta-APP) has led to the development of cellular and animal models that have helped in understanding aspects of the pathophysiology of the inherited early onset forms of AD. However, the majority of AD cases are sporadic with no clear or defined genetic basis. While genetic mutations are responsible for the accumulation of A beta in early onset AD, the causative factors for accumulation of A beta in the late onset AD forms are not known. This raises the possibility that A beta accumulation in the absence of genetic mutations might result from abnormalities that indirectly affect A beta production or its clearance. Currently, there is no consensus as to what are the mechanisms by which A beta accumulates or as to which mechanisms underlie A beta-induced neuronal death in AD. In this review, I will first describe the physiological role of endoplasmic reticulum in the cell and review some of the data supporting dysfunction of the endoplasmic reticulum as an early event leading to A beta accumulation in familial AD. I will also discuss the possible role of oxidative stress and other factors as contributors in A beta accumulation by reducing the clearance of A beta from the endoplasmic reticulum. Finally, I will summarize data that show the endoplasmic reticulum stress as a mechanism underlying exogenous A beta neurotoxicity.