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Genetic studies implicate phagocytosis pathways in microglia to be a major Alzheimer’s disease (AD)-associated process. Microglia phagocytose synapses in AD mouse models, suggesting a role for microglia in region-specific synapse loss, a pathological hallmark of AD. However, whether specific synapses are targeted for elimination, and if so, how, remains to be elucidated. Here, we show that synapses externalize phosphatidylserine (PtdSer) upon challenge by β-amyloid oligomers, which are then selectively engulfed by microglia. Mechanistically, we find that Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is critical for microglia to sense and preferentially engulf AD synapses. In brains of mice and humans, TREM2 dysfunction leads to exacerbation of apoptotic synapses. Our work altogether suggests a fundamental role for microglia as brain-resident macrophages to remove damaged synapses in AD. We provide mechanistic insight into how TREM2 variants associated with increased risk of developing AD may contribute to defective microglia-synapse function.One-Sentence summaryMicroglia selectively engulf synapses in Alzheimer-like mouse brains via PtdSer-TREM2 signaling.

Summary Recent interest in astrocyte activation states has raised the fundamental question of how these cells, normally essential for synapse and neuronal maintenance, become pathogenic. Here, we show that activation of the unfolded protein response (UPR), specifically phosphorylated protein kinase R-like endoplasmic reticulum (ER) kinase (PERK-P) signaling—a pathway that is widely dysregulated in neurodegenerative diseases—generates a distinct reactivity state in astrocytes that alters the astrocytic secretome, leading to loss of synaptogenic function in vitro. Further, we establish that the same PERK-P-dependent astrocyte reactivity state is harmful to neurons in vivo in mice with prion neurodegeneration. Critically, targeting this signaling exclusively in astrocytes during prion disease is alone sufficient to prevent neuronal loss and significantly prolongs survival. Thus, the astrocyte reactivity state resulting from UPR over-activation is a distinct pathogenic mechanism that can by itself be effectively targeted for neuroprotection., Graphical Abstract, Highlights • PERK-eIF2α signaling in astrocytes generates a distinct “UPR”-reactivity state • UPR-reactive astrocytes have an altered secretome, with reduced synaptogenic factors • UPR-reactive astrocytes fail to support synaptogenesis in vitro • Targeting the astrocytic UPR prevents synapse and neuronal loss in prion-diseased mice, Dysregulation of UPR signaling in neurons is a key mediator of neurodegeneration. Smith et al. show that UPR dysregulation in astrocytes impairs their ability to support synapses; modulating astrocytic UPR signaling prevents neuronal loss and increases survival in prion-diseased mice.

Visual detection and color discrimination become more challenging tasks when laser eye protection (LEP) is worn. This is due to the reduced light transmission and wavelength-blocking characteristics of LEP filters. LEP can, however, provide valuable protection against laser eye dazzle—the temporary reduction of vision caused by visible wavelength lasers. To understand this compromise, a model has been developed to allow the visual impacts of LEP to be simulated and balanced against their dazzle protection capabilities. This model is able to use any digital image as a background scene, allowing for real-world visualizations of LEP and dazzle over a broad range of scenarios. The work is built from the CIECAM02 color appearance model and a modified CIE general disability glare equation, together with experimentally validated adjustments to improve the accuracy of this application. The resulting model will help to inform LEP procurement and will serve as an educational tool for LEP users.Visual detection and color discrimination become more challenging tasks when laser eye protection (LEP) is worn. This is due to the reduced light transmission and wavelength-blocking characteristics of LEP filters. LEP can, however, provide valuable protection against laser eye dazzle—the temporary reduction of vision caused by visible wavelength lasers. To understand this compromise, a model has been developed to allow the visual impacts of LEP to be simulated and balanced against their dazzle protection capabilities. This model is able to use any digital image as a background scene, allowing for real-world visualizations of LEP and dazzle over a broad range of scenarios. The work is built from the CIECAM02 color appearance model and a modified CIE general disability glare equation, together with experimentally validated adjustments to improve the accuracy of this application. The resulting model will help to inform LEP procurement and will serve as an educational tool for LEP users.

Activation of the unfolded protein response (UPR) is emerging as a common theme in neurodegenerative diseases, seen in both human brain tissue and mouse models. Genetic and pharmacological manipulation of the pathway in several mouse models has shown that this is not a passive consequence of the neurodegeneration process. Rather, over-activation of the PERK branch of the UPR directly contributes to disease pathogenesis through the critical reduction in neuronal protein synthesis rates via the phosphorylation of eIF2α. eIF2α-P levels are critical to learning and memory in health also; the sustained high levels in neurodegenerative disease results both in impaired learning and memory and to loss of synapse numbers and function essential for neuronal survival. Pharmacological inhibition of this process is strikingly neuroprotective in several models, leading to the discovery of the first small molecule to prevent neurodegeneration in vivo . Critically, this represents a generic approach for boosting memory and the prevention of neurodegeneration through rescue of synapses across the spectrum of these disorders, with few exceptions, independent of disease-specific proteins. Targeting the UPR, and particularly eIF2α-P-mediated translational failure is emerging as a compelling strategy for rescuing synaptic failure and neuronal loss for new treatments for dementia and neurodegenerative disease. This article is part of a Special Issue entitled SI:ER stress .

Diabetic neuropathy is a common secondary complication of diabetes that impacts on patient's health and well-being. Distal axon degeneration is a key feature of diabetic neuropathy, but the pathological changes which underlie axonal die-back are incompletely understood; despite decades of research a treatment has not yet been identified. Basic research must focus on understanding the complex mechanisms underlying changes that occur in the nervous system during diabetes. To this end, tissue culture techniques are invaluable as they enable researchers to examine the intricate mechanistic responses of cells to high glucose or other factors in order to better understand the pathogenesis of nerve dysfunction. This chapter describes the use of in vitro models to study a wide range of specific cellular effects pertaining to diabetic neuropathy including apoptosis, neurite outgrowth, neurodegeneration, activity, and bioenergetics. We consider problems associated with in vitro modeling and future refinement such as use of induced pluripotent stem cells and microfluidic technology.

High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However, our understanding of the molecular mechanisms that cause the marked distal pathology is incomplete. We performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. We integrated proteomics and metabolomics from the sciatic nerve (SN), the lumbar 4/5 dorsal root ganglia (DRG), and the trigeminal ganglia (TG) of streptozotocin-diabetic and healthy control rats. Even though all tissues showed a dramatic increase in glucose and polyol pathway intermediates in diabetes, a striking upregulation of mitochondrial oxidative phosphorylation and perturbation of lipid metabolism was found in the distal SN that was not present in the corresponding cell bodies of the DRG or the cranial TG. This finding suggests that the most severe molecular consequences of diabetes in the nervous system present in the SN, the region most affected by neuropathy. Such spatial metabolic dysfunction suggests a failure of energy homeostasis and/or oxidative stress, specifically in the distal axon/Schwann cell–rich SN. These data provide a detailed molecular description of the distinct compartmental effects of diabetes on the PNS that could underlie the distal-proximal distribution of pathology.