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Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries. Accurate treatment of traumatic brain injuries, a leading cause of neurological disability and death in young people, is hampered by poor accumulation of drugs in the brain. Here, the authors describe a tetrapeptide that can efficiently target brain injuries and deliver therapeutic or diagnostic payload.

Myelin, a multilayered membrane sheath formed by oligodendrocytes around axons in the CNS, enables rapid nerve impulse conduction and sustains neuronal health. The signals exchanged between axons and oligodendrocytes in myelin remain to be fully elucidated. Here we provide genetic evidence for multiple and critical functions of Contactin-1 in central myelin. We document dynamic Contactin-1 expression on oligodendrocytes in vivo, and progressive accumulation at nodes of Ranvier and paranodes during postnatal mouse development. Nodal and paranodal expression stabilized in mature myelin, but overall membranous expression diminished. Contactin-1–deficiency disrupted paranodal junction formation as evidenced by loss of Caspr, mislocalized potassium K ᵥ1.2 channels, and abnormal myelin terminal loops. Reduced numbers and impaired maturation of sodium channel clusters accompanied this phenotype. Histological, electron microscopic, and biochemical analyses uncovered significant hypomyelination in Contactin-1–deficient central nerves, with up to 60% myelin loss. Oligodendrocytes were present in normal numbers, albeit a minor population of neuronal/glial antigen 2-positive (NG2 ⁺) progenitors lagged in maturation by postnatal day 18, when the mouse null mutation was lethal. Major contributing factors to hypomyelination were defects in the generation and organization of myelin membranes, as judged by electron microscopy and quantitative analysis of oligodendrocyte processes labeled by GFP transgenically expressed from the proteolipid protein promoter. These data reveal that Contactin-1 regulates both myelin formation and organization of nodal and paranodal domains in the CNS. These multiple roles distinguish central Contactin-1 functions from its specific role at paranodes in the periphery, and emphasize mechanistic differences in central and peripheral myelination.

The destruction of the myelin sheath that encircles axons leads to impairments of nerve conduction and neuronal dysfunctions. A major demyelinating disorder is multiple sclerosis (MS), a progressively disabling disease in which immune cells attack the myelin. To date, there are no therapies to target selectively myelin lesions, repair the myelin or stop MS progression. Small peptides recognizing epitopes selectively exposed at sites of injury show promise for targeting therapeutics in various pathologies. Here we show the selective homing of the four amino acid peptide, cysteine-alanine-lysine glutamine (CAQK), to sites of demyelinating injuries in three different mouse models. This selective homing was assessed by administrating fluoresceinamine (FAM)-labeled peptide into the blood stream of mice, comparing sites of demyelination with healthy brain or spinal cord tissue. FAM-CAQK selectively targeted demyelinating areas in all three models and was absent from healthy tissue. At lesion sites, the peptide primarily associated with the fibrous extracellular matrix deposited in interstitial spaces proximal to reactive astrocytes. Overlap of FAM-CAQK was detected with Tenascin-C although tenascin depositions made up only a minor portion of the examined lesion sites. In mice on a six-week cuprizone diet, FAM-CAQK peptide crossed the nearly intact blood-brain barrier and homed to demyelinating fiber tracts. These results demonstrate the selective targeting of CAQK to demyelinating injuries under multiple conditions and confirm the previously reported association with the ECM (Mann et al., 2016). This work sets the stage for further developing CAQK peptide targeting for diagnostic and therapeutic applications aimed at localized myelin repair.

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

Synaptic abnormalities and learning dysfunction are prominent characteristics of Down's syndrome. Now Huaxi Xu and colleagues show that expression of the protein SNX27 is reduced in Down's syndrome brains and that restoring its expression can ameliorate learning dysfunction in a mouse model of the disease. Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27 −/− mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27 +/− mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein β (C/EBPβ) in Down's syndrome brains and identify C/EBPβ as a transcription factor for SNX27 . Down's syndrome causes overexpression of miR-155, a chromosome 21–encoded microRNA that negatively regulates C/EBPβ, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.

Voltage-gated Na + channel (VGSC) β1 subunits regulate cell–cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na + current (I Na ) mediated by Na v 1.6. In addition, β1 is required for high-frequency action potential firing. Transient I Na is unchanged in Scn1b (β1) null CGNs; however, the resurgent I Na , thought to underlie high-frequency firing in Na v 1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Na v 1.6 is reduced in Scn1b null cerebellar neurons. In place of Na v 1.6 at the AIS, we observed an increase in Na v 1.1, whereas Na v 1.2 was unchanged. This indicates that β1 is required for normal localization of Na v 1.6 at the AIS during the postnatal developmental switch to Na v 1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Na v 1.6 such that β1-mediated neurite outgrowth requires Na v 1.6-mediated I Na , and Na v 1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.

Neuronal regulation of diverse physiological functions requires complex molecular interactions in innervated tissues to maintain proper organ function. Here we show that loss of the neuronal cell surface adhesion/recognition molecule Contactin-1 ( directly impairs intestinal function causing wasting that subsequently results in global immune defects. Loss of results in hematologic alterations and changes in blood metabolites associated with malnourishment. We found thymus and spleen of -deficient animals atrophied with severe reductions in lymphocyte populations. Elevated thymic expression indicated ongoing glucocorticoid signaling in -deficient animals, consistent with the malnourishment phenotype. Intestinal Contactin-1 was localized to neurons in the villi and the submucosal/myenteric plexus that innervates smooth muscle. Loss of was associated with reduced intestinal and , indicating reduced neuromuscular crosstalk. Additionally, loss of resulted in reduced recruitment of CD3 T cells to villi within the small intestine. Together, these data illustrate the critical role of Contactin-1 function within the gut, and how this is required for normal systemic immune functions.

The Cadherin 13 ( CDH13 ) gene encodes a cell adhesion molecule likely to influence development and connections of brain circuits that modulate addiction, locomotion and cognition, including those that involve midbrain dopamine neurons. Human CDH13 mRNA expression differs by more than 80% in postmortem cerebral cortical samples from individuals with different CDH13 genotypes, supporting examination of mice with altered CDH13 expression as models for common human variation at this locus. Constitutive CDH13 knockout mice display evidence for changed cocaine reward: shifted dose response relationship in tests of cocaine-conditioned place preference using doses that do not alter cocaine-conditioned taste aversion. Reduced adult CDH13 expression in conditional knockouts also alters cocaine reward in ways that correlate with individual differences in cortical CDH13 mRNA levels. In control and comparison behavioral assessments, knockout mice display modestly quicker acquisition of rotarod and water maze tasks, with a trend toward faster acquisition of 5-choice serial reaction time tasks that otherwise displayed no genotype-related differences. They display significant differences in locomotion in some settings, with larger effects in males. In assessments of brain changes that might contribute to these behavioral differences, there are selective alterations of dopamine levels, dopamine/metabolite ratios, dopaminergic fiber densities and mRNA encoding the activity dependent transcription factor npas4 in cerebral cortex of knockout mice. These novel data and previously reported human associations of CDH13 variants with addiction, individual differences in responses to stimulant administration and attention deficit hyperactivity disorder (ADHD) phenotypes suggest that levels of CDH13 expression, through mechanisms likely to include effects on mesocortical dopamine, influence stimulant reward and may contribute modestly to cognitive and locomotor phenotypes relevant to ADHD.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Adiponectin is an adipose derived hormone that declines in obesity. We have previously shown that exogenous administration of adiponectin reduces allergic airways responses in mice. T-cadherin (T-cad; Cdh13) is a binding protein for the high molecular weight isoforms of adiponectin. To determine whether the beneficial effects of adiponectin on allergic airways responses require T-cad, we sensitized wildtype (WT), T-cadherin deficient (T-cad(-/-)) and adiponectin and T-cad bideficient mice to ovalbumin (OVA) and challenged the mice with aerosolized OVA or PBS. Compared to WT, T-cad(-/-) mice were protected against OVA-induced airway hyperresponsiveness, increases in BAL inflammatory cells, and induction of IL-13, IL-17, and eotaxin expression. Histological analysis of the lungs of OVA-challenged T-cad(-/-) versus WT mice indicated reduced inflammation around the airways, and reduced mucous cell hyperplasia. Combined adiponectin and T-cad deficiency reversed the effects of T-cad deficiency alone, indicating that the observed effects of T-cad deficiency require adiponectin. Compared to WT, serum adiponectin was markedly increased in T-cad(-/-) mice, likely because adiponectin that is normally sequestered by endothelial T-cad remains free in the circulation. In conclusion, T-cad does not mediate the protective effects of adiponectin. Instead, mice lacking T-cad have reduced allergic airways disease, likely because elevated serum adiponectin levels act on other adiponectin signaling pathways.