Unfolded protein response as a target in the treatment of Alzheimer's disease

The clinical features of Alzheimer's disease (AD), for example the progressive memory loss, are produced by neuronal loss and synaptic dysfunction. These events have been associated with histopathological alterations in AD brain, including the presence of amyloid plaques and neurofibrillary tangles. Recent studies suggest that cellular stress produced by the aggregation of misfolded proteins leads to alterations in protein homeostasis, that is regulated for the most part by endoplasmic reticulum (ER). The ER is the main compartment involved in the folding and secretion of proteins and is drastically affected in AD neurons. Recent evidence implicates the participation of adaptive responses to stress within the ER in the disease process through a signaling pathway known as the Unfolded Protein Response (UPR) which alleviates the protein aggregation and ER stress. Based on the involvement of ER stress in several diseases, efforts are being done to identify small molecules that can inhibit or activate selective UPR components. Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.