Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M^pro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M^pro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M^pro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with α-secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid β (Aβ) peptide in Alzheimer′s disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPα and increased levels of sAPPβ and endogenous Aβ peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.

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 (PrP^C) 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 PrP^C connects to protective functions attributed to exosomes in Alzheimer's disease. To achieve this, we generated a mouse neuroblastoma PrP^C knockout cell line using transcription activator‐like effector nucleases. Using these, as well as SH‐SY5Y human neuroblastoma cells, we show that PrP^C is highly enriched on exosomes and that exosomes bind amyloid beta via PrP^C. Exosomes showed highest binding affinity for dimeric, pentameric, and oligomeric Aβ species. Thioflavin T assays revealed that exosomal PrP^C 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 PrP^C in molecular mechanisms of Alzheimer's disease. image We show that the prion protein (PrP^C) 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, PrP^C 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 PrP^C in Alzheimer's disease. Read the Editorial Highlight for this article on page 9.Cover Image for this issue: doi: 10.1111/jnc.13312.

Alzheimer’s disease is the most common form of dementia and the generation of oligomeric species of amyloid-β is causal to the initiation and progression of it. Amyloid-β oligomers bind to the N-terminus of plasma membrane-bound cellular prion protein (PrP^C) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-β oligomers, binding regions within PrP^C, binding affinities and modifiers of this interaction have been almost exclusively studied in cell culture or murine models of Alzheimer’s disease and our knowledge on PrP^C-amyloid-β interaction in patients with Alzheimer’s disease is limited regarding occurrence, binding regions in PrP^C, and size of bound amyloid-β oligomers. Here we employed a PrP^C-amyloid-β binding assay and size exclusion chromatography on neuropathologically characterized Alzheimer’s disease and non-demented control brains (n = 15, seven female, eight male, average age: 79.2 years for Alzheimer’s disease and n = 10, three female, seven male, average age: 66.4 years for controls) to investigate amyloid-β-PrP^C interaction. PrP^C-amyloid-β binding always occurred in Alzheimer’s disease brains and was never detected in non-demented controls. Neither expression level of PrP^C nor known genetic modifiers of Alzheimer’s disease, such as the PrP^C codon 129 polymorphism, influenced this interaction. In Alzheimer’s disease brains, binding of amyloid-β to PrP^C occurred via the PrP^C N-terminus. For synthetic amyloid-β₄₂, small oligomeric species showed prominent binding to PrP^C, whereas in Alzheimer’s disease brains larger protein assemblies containing amyloid-β₄₂ bound efficiently to PrP^C. These data confirm Alzheimer’s disease specificity of binding of amyloid-β to PrP^C via its N-terminus in a large cohort of Alzheimer’s disease/control brains. Differences in sizes of separated protein fractions between synthetic and brain-derived amyloid-β binding to PrP^C suggest that larger assemblies of amyloid-β or additional non-amyloid-β components may play a role in binding of amyloid-β₄₂ to PrP^C in Alzheimer’s disease.

Significance: Our report highlights, for the first time to our knowledge, a distinct relationship between lysosomal integral membrane protein type-2 (LIMP-2) expression, β-glucocerebrosidase (GC) activity, and clearance of α-synuclein. In LIMP-2–deficient mice, increased levels of endogenous α-synuclein led to severe neurological deficits and premature death. We found that loss of LIMP-2 reduced lysosomal GC activity, resulting in lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation leading to neurotoxicity of dopaminergic neurons as well as apoptotic cell death and inflammation. Furthermore, heterologous overexpression of functional LIMP-2 enhanced α-synuclein clearance and improved lysosomal activity of GC. Our results suggest that lysosomal GC activity can be influenced via its interaction with LIMP-2, which could be a promising strategy for the treatment of synucleinopathies.

Background: The cellular prion protein (PrP^C) fulfils several yet not completely understood physiological functions. Apart from these functions, it has the ability to misfold into a pathogenic scrapie form (PrP^Sc) leading to fatal transmissible spongiform encephalopathies. Proteolytic processing of PrP^C generates N- and C-terminal fragments which play crucial roles both in the pathophysiology of prion diseases and in transducing physiological functions of PrP^C. A-disintegrin-and-metalloproteinase 10 (ADAM10) has been proposed by cell culture experiments to be responsible for both shedding of PrP^C and its α-cleavage. Here, we analyzed the role of ADAM10 in the proteolytic processing of PrP^C in vivo. Results: Using neuron-specific Adam10 knockout mice, we show that ADAM10 is the sheddase of PrP^C and that its absence in vivo leads to increased amounts and accumulation of PrP^C in the early secretory pathway by affecting its posttranslational processing. Elevated PrP^C levels do not induce apoptotic signalling via p53. Furthermore, we show that ADAM10 is not responsible for the α-cleavage of PrP^C. Conclusion: Our study elucidates the proteolytic processing of PrP^C and proves a role of ADAM10 in shedding of PrP^C in vivo. We suggest that ADAM10 is a mediator of PrP^C homeostasis at the plasma membrane and, thus, might be a regulator of the multiple functions discussed for PrP^C. Furthermore, identification of ADAM10 as the sheddase of PrP^C opens the avenue to devising novel approaches for therapeutic interventions against prion diseases.