Accumulation of β-amyloid (Aβ) peptide in the brain is suggested to play a key role in the
pathogenesis of Alzheimer’s disease (AD). Both the inherited familial and the sporadic forms of AD
are characterized by increased levels of Aβ42. Incubation of cells with synthetic Aβ or administration
of this peptide to animals is also associated with cellular degeneration. Currently, the mechanisms by
which Aβ accumulates as well as the mechanisms that underlie Aβ-induced neurodegeneration in AD
are not fully understood. Aβ is generated in part in the endoplasmic reticulum of neurons, degraded
chiefely by the insulin degrading enzyme, and cleared out of the brain primarily by the low-density
lipoprotein receptor-related protein. Stress in the endoplasmic reticulum can affect the processes
involved in Aβ generation, degradation, and clearance, thus resulting in increased levels of this
peptide in the brain. In this chapter, first, supportive data of role of disturbances in the endoplasmic
reticulum homeostasis as an underlying mechanism of Aβ accumulation will be provided. Second,
evidence from in vitro and in vivo studies showing that the endoplasmic reticulum is a target organelle
for exogenous Aβ will be demonstrated. When applied to cells or administered to animals Aβ triggers
endoplasmic reticulum stress that is ultimately deleterious to cells. Collectively, data from AD brains,
animal models for AD, and in vitro studies converge to present compelling evidence that the
endoplasmic reticulum stress is relevant to the pathogenesis of AD.
