XBP1 to Upregulate the Unfolded Protein Response Reduces Pathology in Mouse Models of Alzheimer's Disease
Overexpression of the transcription factor XBP1 has been shown to extend life in flies. It is thought to achieve this outcome by increasing the efficiency of the unfolded protein response, a cell maintenance process. Its diverse other effects may also be important, as its regulation of transcription touches on immune function, lipid metabolism, glucose metabolism, and other mechanisms. This extensive portfolio of influences is often the case for transcription factors. Here, researchers apply brain-specific XBP1 overexpression to mouse models of Alzheimer's disease, and observe a reduction in pathology.
The decay of the proteostasis network has been pointed out as a primary hallmark of aging, a phenomenon that may contribute to Alzheimer's disease (AD) pathogenesis. Strategies to improve proteostasis have been tested in multiple models of neurodegenerative diseases, observing outstanding protective effects. One of the central nodes of the proteostasis network altered during aging involves the function of the endoplasmic reticulum (ER), the main site for protein production in the cell. The ER is also highly altered in AD. To cope with ER stress, cells activate an evolutionarily conserved pathway known as the unfolded protein response (UPR), which aims to re-establish proteostasis. The UPR reinforces many processes involved in the function of the secretory pathway to improve protein production and sustain cell function, whereas chronic ER stress results in neurodegeneration and cell death.
The most conserved UPR signaling branch is initiated by the ER stress sensor IRE1, which catalyzes the unconventional splicing of the mRNA encoding XBP1. This event results in the expression of an active transcription factor, termed XBP1s, which enables transcriptional reprogramming. We recently reported that the activity of the IRE1/XBP1 pathway declines in the brain during normal aging in mammals and strategies to enhance the activity of the UPR extend brain healthspan. Importantly, we showed that strategies to express XBP1s in neurons either using transgenic mice or gene therapy delayed synaptic dysfunction and cognitive decline during normal aging, in addition to reducing the content of senescence cells in the brain.
With the idea of testing the effects of artificially enforcing UPR adaptive responses in the AD brain, we overexpressed the active XBP1s form in the nervous system using transgenic mice, in addition to the hippocampus using adeno-associated viral (AAV) vectors. Overexpression of XBP1s dramatically reduced the content of amyloid plaques in the brain and improved cognitive performance and synaptic plasticity in a model of familial AD (5xFAD transgenic animals expressing mutant APP and presenilin-1). Additionally, XBP1s overexpression in the brain improved memory performance on a model of sporadic AD based on the injection of amyloid β oligomers. The beneficial effects of XBP1s expression in the context of experimental AD and normal aging involve a substantial correction of gene expression patterns associated with synaptic function, neuronal morphology, and connectivity. Thus, we speculate that a major protective mechanism of XBP1s in AD relates to its function as a regulator of neuronal physiology that may parallel its effects in reducing amyloid deposition.