Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by progressive loss
of memory and cognitive impairment. Aggregation of amyloid-β (Aβ) peptides is the crucial factor in the onset of AD.
The toxic Aβ peptides Aβ40 and Aβ42 are produced from the Aβ precursor protein (APP), a transmembrane protein which
is folded and modified in endoplasmic reticulum (ER). ER is the main organelle for the synthesis and processing of nearly
all proteins as well as the main cellular source of Ca2+. Under stress conditions, three main ER pathways including inositol-
requiring enzyme 1, protein kinase RNA-like ER kinase, and activating transcription factor 6 become activated causing
the accumulation of unfolded or misfolded proteins within ER lumen. These pathways manage the stress by regulating
the expression of chaperones and enzymes involved in protein folding. Several studies have reported the dysfunction of
these stress-sensing pathways in pathological conditions, including neurodegenerative diseases. Recent studies have proposed
that neuronal death in AD arises from dysfunction of the ER. Here, we will review recent research findings on the
interaction between ER and mitochondria, and its effect on apoptotic pathways. We further provide insights into studies
which suggest the role of ER in animal and/or cellular models of AD. Therapeutic strategies that modulate ER could represent
a promising approach for prevention or treatment of AD.