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Current Molecular Medicine
ISSN (Print): 1566-5240
ISSN (Online): 1875-5666
VOLUME: 6
ISSUE: 1
DOI: 10.2174/156652406775574514









The Role of the Endoplasmic Reticulum in the Accumulation of β-Amyloid Peptide in Alzheimers Disease

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Author(s): Othman Ghribi
Pages 119-133 (15)
Abstract:
Increased cerebral levels of Aβ42 peptide, either as soluble or aggregated forms, are suggested to play a key role in the pathogenesis of Alzheimers disease (AD). The identification of genetic defects in presenilins and β-amyloid precursor protein (β-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 Aβ in early onset AD, the causative factors for accumulation of Aβ in the late onset AD forms are not known. This raises the possibility that Aβ accumulation in the absence of genetic mutations might result from abnormalities that indirectly affect Aβ production or its clearance. Currently, there is no consensus as to what are the mechanisms by which Aβ accumulates or as to which mechanisms underlie Aβ-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 Aβ accumulation in familial AD. I will also discuss the possible role of oxidative stress and other factors as contributors in Aβ accumulation by reducing the clearance of Aβ from the endoplasmic reticulum. Finally, I will summarize data that show the endoplasmic reticulum stress as a mechanism underlying exogenous Aβ neurotoxicity.
Keywords:
Aβ, Alzheimer's disease, calcium, calreticulin, endoplasmic reticulum, ERAD, gadd153, UPR
Affiliation:
Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, North Dakota 58202, USA.