Altered proteostasis is a salient feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid β oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention.

As a “holy grail” of neuroscience, optical imaging of membrane potential could enable high resolution measurements of spiking and synaptic activity in neuronal populations. This has been partly achieved using organic voltage-sensitive dyes in vitro, or in invertebrate preparations yet unspecific staining has prevented single-cell resolution measurements from mammalian preparations in vivo. The development of genetically encoded voltage indicators (GEVIs) and chemogenetic sensors has enabled targeting voltage indicators to plasma membranes and selective neuronal populations. Here, we review recent advances in the design and use of genetic voltage indicators and discuss advantages and disadvantages of three classes of them. Although genetic voltage indicators could revolutionize neuroscience, there are still significant challenges, particularly two-photon performance. To overcome them may require cross-disciplinary collaborations, team effort, and sustained support by large-scale research initiatives.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR). 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.

Dendritic spines’ electrical function? Dendritic spines are small protrusions that cover the dendrites of most neurons in the brain. Their electrical properties are still controversially discussed. Cornejo et al . used an array of techniques to investigate the degree of voltage attenuation by dendritic spine necks in pyramidal neurons of the mouse neocortex. Spines not only synchronously depolarized in response to backpropagating action potentials, but local and transient depolarization also occurred. Isolated depolarization in individual spines reflected localized synaptic activation. A significant voltage gradient between dendritic spine and dendrite indicated that spines may constitute elementary electric compartments. The spine neck resistance is thus not negligible and may substantially contribute to the regulation of synaptic efficacy in the central nervous system. —PRS

Background: ERp57 is a disulfide isomerase up-regulated in prion related-disorders, but its impact on PrP biology is unknown. Results: ERp57 gain-and loss-of-function can increase or reduce, respectively, PrP levels in neurons, both in cell culture and animal models. Conclusion: ERp57 regulates steady-state prion protein levels. Significance: ERp57 is a cellular factor involved in the synthesis and folding of PrP, representing a novel therapeutic target in prion-related diseases.