Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent ...molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer’s disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
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•Microglia associated with neuritic Aβ-plaques exhibit a neurodegenerative phenotype•Phagocytosis of apoptotic neurons suppresses homeostatic microglia•The TREM2-APOE pathway regulates neurodegenerative microglial phenotypic switch•Targeting APOE signaling restores homeostatic and tolerogenic microglia
Microglia change their phenotype and function during aging and neurodegeneration, but the underlying molecular mechanisms for this change remain unknown. Krasemann et al. identify the TREM2-APOE pathway as a major regulator of microglia phenotypic change in neurodegenerative diseases and suggest that targeting this pathway could restore homeostatic microglia.
Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious ...proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.
Metastatic seeding is driven by cell-intrinsic and environmental cues, yet the contribution of biomechanics is poorly known. We aim to elucidate the impact of blood flow on the arrest and the ...extravasation of circulating tumor cells (CTCs) in vivo. Using the zebrafish embryo, we show that arrest of CTCs occurs in vessels with favorable flow profiles where flow forces control the adhesion efficacy of CTCs to the endothelium. We biophysically identified the threshold values of flow and adhesion forces allowing successful arrest of CTCs. In addition, flow forces fine-tune tumor cell extravasation by impairing the remodeling properties of the endothelium. Importantly, we also observe endothelial remodeling at arrest sites of CTCs in mouse brain capillaries. Finally, we observed that human supratentorial brain metastases preferably develop in areas with low perfusion. These results demonstrate that hemodynamic profiles at metastatic sites regulate key steps of extravasation preceding metastatic outgrowth.
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•Arrest of circulating tumor cells occurs in blood vessels with permissive flow profiles•pN-range adhesion forces favor rapid and stable intravascular adhesion•Flow-mediated endothelial remodeling drives extravasation of tumor cells
Follain et al. demonstrate that blood flow forces tune both the arrest and extravasation of circulating tumor cells in vivo. Permissive flow forces allow stable intravascular arrest of circulating tumor cells. Flow forces drive endothelial remodeling around arrested tumor cells, favoring extravasation preceding metastatic outgrowth.
Exosomes are involved in the progression of neurodegenerative diseases. The cellular prion protein (PrP
) is highly expressed on exosomes. In neurodegenerative diseases, PrP
has at least two ...functions: It is the substrate for the generation of pathological prion protein (PrP
), a key player in the pathophysiology of prion diseases. On the other hand, it binds neurotoxic amyloid-beta (Aß) oligomers, which are associated with initiation and progression of Alzheimer's disease (AD). This has direct consequences for the role of exosomal expressed PrP
. In prion diseases, exosomal PrP leads to efficient dissemination of pathological prion protein, thus promoting spreading and transmission of the disease. In AD, exosomal PrP
can bind and detoxify Aß oligomers thus acting protective. In both scenarios, assessment of the state of PrP
on exosomes derived from blood or cerebrospinal fluid (CSF) may be useful for diagnostic workup of these diseases. This review sums up current knowledge of the role of exosomal PrP
on different aspects of Alzheimer's and prion disease.
The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield ...fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer’s disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.
Alzheimer's disease is a common neurodegenerative, progressive, and fatal disorder. Generation and deposition of amyloid beta (Aβ) peptides associate with its pathogenesis and small soluble Aβ ...oligomers show the most pronounced neurotoxic effects and correlate with disease initiation and progression. Recent findings showed that Aβ oligomers bind to the cellular prion protein (PrPC) eliciting neurotoxic effects. The role of exosomes, small extracellular vesicles of endosomal origin, in Alzheimer's disease is only poorly understood. Besides serving as disease biomarkers they may promote Aβ plaque formation, decrease Aβ‐mediated synaptotoxicity, and enhance Aβ clearance. Here, we explore how exosomal PrPC connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrPC knockout cell line using transcription activator‐like effector nucleases. Using these, as well as SH‐SY5Y human neuroblastoma cells, we show that PrPC is highly enriched on exosomes and that exosomes bind amyloid beta via PrPC. Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric Aβ species. Thioflavin T assays revealed that exosomal PrPC accelerates fibrillization of amyloid beta, thereby reducing neurotoxic effects imparted by oligomeric Aβ. Our study provides further evidence for a protective role of exosomes in Aβ‐mediated neurodegeneration and highlights the importance of exosomal PrPC in molecular mechanisms of Alzheimer's disease.
We show that the prion protein (PrPC) on exosomes captures neurotoxic species of amyloid beta (Aβ) promoting its fibrillization. Our study provides evidence for a protective role of exosomes in Alzheimer`s disease and suggests that, depending on its membrane topology, PrPC holds a dual function: when expressed at the neuronal surface it acts as receptor for Aβ leading to neurotoxic signaling, whereas it detoxifies Aβ when present on exosomes. This provides further support for key roles of PrPC in Alzheimer's disease.
Read the Editorial Highlight for this article on page 9.
Cover Image for this issue: doi: 10.1111/jnc.13312.
We show that the prion protein (PrPC) on exosomes captures neurotoxic species of amyloid beta (Aβ) promoting its fibrillization. Our study provides evidence for a protective role of exosomes in Alzheimer`s disease and suggests that, depending on its membrane topology, PrPC holds a dual function: when expressed at the neuronal surface it acts as receptor for Aβ leading to neurotoxic signaling, whereas it detoxifies Aβ when present on exosomes. This provides further support for key roles of PrPC in Alzheimer's disease.
Read the Editorial Highlight for this article on page 9.
Cover Image for this issue: doi: 10.1111/jnc.13312.
The devastating effect of ischemic stroke is attenuated in mice lacking conventional and unconventional T cells, suggesting that inflammation enhances tissue damage in cerebral ischemia. We explored ...the functional role of αβ and γδ T cells in a murine model of stroke and distinguished 2 different T cell–dependent proinflammatory pathways in ischemia-reperfusion injury. IFN-γ produced by CD4+ T cells induced TNF-α production in macrophages, whereas IL-17A secreted by γδ T cells led to neutrophil recruitment. The synergistic effect of TNF-α and IL-17A on astrocytes resulted in enhanced secretion of CXCL-1, a neutrophil chemoattractant. Application of an IL-17A–blocking antibody within 3 hours after stroke induction decreased infarct size and improved neurologic outcome in the murine model. In autoptic brain tissue of patients who had a stroke, we detected IL-17A–positive lymphocytes, suggesting that this aspect of the inflammatory cascade is also relevant in the human brain. We propose that selective targeting of IL-17A signaling might provide a new therapeutic option for the treatment of stroke.
Proteolytic processing of the cellular and disease-associated form of the prion protein leads to generation of bioactive soluble prion protein fragments and modifies the structure and function of its ...cell-bound form. The nature of proteases responsible for shedding, α-, β-, and γ-cleavage of the prion protein are only partially identified and their regulation is largely unknown. Here, we provide an overview of the increasingly multifaceted picture of prion protein proteolysis and shed light on physiological and pathological roles associated with these cleavages. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.
•Conserved proteolytic processing events occur on the cellular prion protein (PrPC).•Proteolytic cleavages may account for the multitude of functions attributed to PrPC.•Processing of the prion protein also impacts on neurodegenerative diseases.•Stimulation of two cleavages may be beneficial in neurodegeneration and beyond.
Chemotherapy of glioblastoma is largely ineffective as the blood-brain barrier (BBB) prevents entry of most anticancer agents into the brain. For an efficient treatment of glioblastomas it is ...necessary to deliver anti-cancer drugs across the intact BBB. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with poloxamer 188 hold great promise as drug carriers for brain delivery after their intravenous injection. In the present study the anti-tumour efficacy of the surfactant-coated doxorubicin-loaded PLGA nanoparticles against rat glioblastoma 101/8 was investigated using histological and immunohistochemical methods.
The particles were prepared by a high-pressure solvent evaporation technique using 1% polyvinylalcohol (PLGA/PVA) or human serum albumin (PLGA/HSA) as stabilizers. Additionally, lecithin-containing PLGA/HSA particles (Dox-Lecithin-PLGA/HSA) were prepared. For evaluation of the antitumour efficacy the glioblastoma-bearing rats were treated intravenously with the doxorubicin-loaded nanoparticles coated with poloxamer 188 using the following treatment regimen: 3 × 2.5 mg/kg on day 2, 5 and 8 after tumour implantation; doxorubicin and poloxamer 188 solutions were used as controls. On day 18, the rats were sacrificed and the antitumour effect was determined by measurement of tumour size, necrotic areas, proliferation index, and expression of GFAP and VEGF as well as Isolectin B4, a marker for the vessel density.
The results reveal a considerable anti-tumour effect of the doxorubicin-loaded nanoparticles. The overall best results were observed for Dox-Lecithin-PLGA/HSA. These data demonstrate that the poloxamer 188-coated PLGA nanoparticles enable delivery of doxorubicin across the blood-brain barrier in the therapeutically effective concentrations.
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