The neuronal cell adhesion molecule ICAM-5

The neuronal cell adhesion molecule ICAM-5 ICAM-5 (telencephalin) belongs to the intercellular adhesion molecule (ICAM)-subgroup of the immunoglobulin superfamily (IgSF). ICAMs participate in leukocyte adhesion and adhesion-dependent functions in the central nervous system (CNS) through interacting with the leukocyte-specific b2 integrins. ICAM-5 is found in the mammalian forebrain, appears at the time of birth, and is located at the cell soma and neuronal dendrites. Recent studies also show that it is important for the regulation of immune functions in the brain and for the development and maturation of neuronal synapses. The clinical importance of ICAM-5 is still under investigation; it may have a role in the development of Alzheimer s disease (AD). In this study, the role of ICAM-5 in neuronal differentiation and its associations with a-actinin and N-methyl-D-aspartic acid (NMDA) receptors were examined. NMDA receptors (NMDARs) are known to be involved in many neuronal functions, including the passage of information from one neuron to another one, and thus it was thought important to study their role related to ICAM-5. The results suggested that ICAM-5 was able to induce dendritic outgrowth through homophilic adhesion (ICAM-5 monomer binds to another ICAM-5 monomer in the same or neighbouring cell), and the homophilic binding activity appeared to be regulated by monomer/multimer transition. Moreover, ICAM-5 binding to a-actinin was shown to be important for neuritic outgrowth. It was examined whether matrix metalloproteinases (MMPs) are the main enzymes involved in ICAM-5 ectodomain cleavage. The results showed that stimulation of NMDARs leads to MMP activation, cleavage of ICAM-5 and it is accompanied by dendritic spine maturation. These findings also indicated that ICAM-5 and NMDA receptor subunit 1 (NR1) compete for binding to a-actinin, and ICAM-5 may regulate the NR1 association with the actin cytoskeleton. Thus, it is concluded that ICAM-5 is a crucial cell adhesion molecule involved in the development of neuronal synapses, especially in the regulation of dendritic spine development, and its functions may also be involved with memory formation and learning.Soluadheesiomolekyyli ICAM-5 Soluadheesiomolekyylit ja solunulkoisen matriksin molekyylit ovat tärkeitä, koska ne osallistuvat mm. solunsisäiseen signaalinvälitykseen sekä solujen väliseen adheesioon. Keskushermostossa yhteydet solun pintaproteiinien ja solunsisäisen aktiinitukirangan ja solun tukirangan proteiinien välillä vaikuttavat hermosolujen migraatioon, synapsien muodostumiseen ja synaptiseen plastisuuteen. Tämä väitöskirja keskittyy tarkastelemaan ICAM-molekyylejä (solujenväliset adheesiomolekyylit), erityisesti ICAM-5-proteiinia. ICAM-5 (telenkefaliini) kuuluu ICAM-perheeseen, joka on osa immunoglobuliinien superperhettä. ICAM-proteiinit osallistuvat leukosyyttien adheesioon ja adheesiosta riippuviin tehtäviin keskushermostossa sitoutumalla leukosyyttispesifisiin b2-integriineihin. ICAM-5 ekspressoituu nisäkkään etuaivoissa syntymän aikoihin ja se lokalisoituu hermosolun soomaan ja dendriitteihin. Se on myös tärkeä molekyyli keskushermoston immuunipuolustuksen säätelyssä ja hermosolujen synapsien kehittymisessä. ICAM-5:n kliininen merkitys on vielä epäselvä; se saattaa osallistua Alzheimerin taudin kehittymiseen. Tässä väitöskirjassa tutkittiin ICAM-5:n roolia hermosolujen kehittymisen aikana sekä sen assosiaatioita alfa-aktiniinin ja NMDA-reseptorien kanssa. NMDA-reseptorit osallistuvat moniin keskushermoston toimintoihin, mm. hermoimpulssien välittämiseen kahden hermosolun välillä synapseissa. Tulosten perusteella ICAM-5 pystyi saamaan aikaan dendriittien kasvua homofiilisen sitoutumisen (ICAM-5 monomeeri sitoutuu toiseen ICAM-5 monomeeriin samassa tai viereisessä hermosolussa) avulla. ICAM-5:n esiintyminen monomeerinä ja multimeerinä näytti säätelevän homofiilistä sitoutumista. Lisäksi tulokset osoittivat, että ICAM-5:n sitoutuminen alfa-aktiniiniin oli tärkeää neuriittien kasvun kannalta. Myös MMP-entsyymien (matriksin metalloproteinaasit) osuutta ICAM-5:n solunulkoisen osan irtoamisessa tutkittiin. Tulosten perusteella näyttää siltä, että NMDA-reseptorien stimulaatio johtaa MMP-entsyymien aktivoitumiseen, jonka seurauksena ICAM-5:n solunulkoinen osa irtoaa solukalvolta ja dendriittiset ulokkeet kehittyvät näiden tapahtumien johdosta. Tulokset osoittivat myös, että ICAM-5 ja NMDA-reseptorin alayksikkö 1 (NR1) kilpailevat sitoutumisesta alfa-aktiniiniin ja ICAM-5 voi mahdollisesti säädellä NR1:n assosiaatiota aktiinitukirangan kanssa. ICAM-5 on tärkeä soluadheesiomolekyyli, joka osallistuu synapsien kehittymiseen ja erityisesti dendriittisten ulokkeiden kehittymisen säätelyyn. Se voi mahdollisesti myös molekulaarisella tasolla osallistua muistin muodostumis- ja oppimistapahtumiin keskushermostossa

ICAM-5 affects spine maturation by regulation of NMDA receptor binding to alpha-actinin

ICAM-5 is a negative regulator of dendritic spine maturation and facilitates the formation of filopodia. Its absence results in improved memory functions, but the mechanisms have remained poorly understood. Activation of NMDA receptors induces ICAM-5 ectodomain cleavage through a matrix metalloproteinase (MMP)-dependent pathway, which promotes spine maturation and synapse formation. Here, we report a novel, ICAM-5-dependent mechanism underlying spine maturation by regulating the dynamics and synaptic distribution of a-actinin. We found that GluN1 and ICAM-5 partially compete for the binding to alpha-actinin; deletion of the cytoplasmic tail of ICAM-5 or ablation of the gene resulted in increased association of GluN1 with alpha-actinin, whereas internalization of ICAM-5 peptide perturbed the GluN1/alpha-actinin interaction. NMDA treatment decreased alpha-actinin binding to ICAM-5, and increased the binding to GluN1. Proper synaptic distribution of alpha-actinin requires the ICAM-5 cytoplasmic domain, without which alpha-actinin tended to accumulate in filopodia, leading to F-actin reorganization. The results indicate that ICAM-5 retards spine maturation by preventing reorganization of the actin cytoskeleton, but NMDA receptor activation is sufficient to relieve the brake and promote the maturation of spines.Peer reviewe

Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage

Matrix metalloproteinase (MMP)-2 and -9 are pivotal in remodeling many tissues. However, their functions and candidate substrates for brain development are poorly characterized. Intercellular adhesion molecule-5 (ICAM-5; Telencephalin) is a neuronal adhesion molecule that regulates dendritic elongation and spine maturation. We find that ICAM-5 is cleaved from hippocampal neurons when the cells are treated with N-methyl-d-aspartic acid (NMDA) or α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA). The cleavage is blocked by MMP-2 and -9 inhibitors and small interfering RNAs. Newborn MMP-2– and MMP-9–deficient mice brains contain more full-length ICAM-5 than wild-type mice. NMDA receptor activation disrupts the actin cytoskeletal association of ICAM-5, which promotes its cleavage. ICAM-5 is mainly located in dendritic filopodia and immature thin spines. MMP inhibitors block the NMDA-induced cleavage of ICAM-5 more efficiently in dendritic shafts than in thin spines. ICAM-5 deficiency causes retraction of thin spine heads in response to NMDA stimulation. Soluble ICAM-5 promotes elongation of dendritic filopodia from wild-type neurons, but not from ICAM-5–deficient neurons. Thus, MMPs are important for ICAM-5–mediated dendritic spine development

Intercellular Adhesion Molecule-5 Induces Dendritic Outgrowth by Homophilic Adhesion

Intercellular adhesion molecule-5 (ICAM-5) is a dendritically polarized membrane glycoprotein in telencephalic neurons, which shows heterophilic binding to leukocyte b2-integrins. Here, we show that the human ICAM-5 protein interacts in a homophilic manner through the binding of the immunoglobulin domain 1 to domains 4–5. Surface coated ICAM-5-Fc promoted dendritic outgrowth and arborization of ICAM- 5–expressing hippocampal neurons. During dendritogenesis in developing rat brain, ICAM-5 was in monomer form, whereas in mature neurons it migrated as a high molecular weight complex. The findings indicate that its homophilic binding activity was regulated by nonmonomer/monomer transition. Thus, ICAM-5 displays two types of adhesion activity, homophilic binding between neurons and heterophilic binding between neurons and leukocytes

Urinary incontinence and its management in patients aged 65 and older in orthopaedic care - what nursing and rehabilitation staff know and do

Aims and objectives: To describe what nursing and rehabilitation staff know and do with regard to urinary incontinence and risk of urinary incontinence in patients 65 years or older undergoing hip surgery. Background: Urinary incontinence is a common but often neglected issue for older people. Despite the existence of evidence-based guidelines on how to assess, manage and prevent urinary incontinence, there are indications that these guidelines are not applied in hospital care. Design: A qualitative study with descriptive design was conducted in two orthopaedic units. Methods: Forty-six interviews and 36 observations of care were conducted from January-October 2014 and analysed with qualitative content analysis. Results: Enrolled nurses performed most of the care related to bladder function, with focus on urinary catheterisation and preventing urinary tract infection and urinary retention. Registered nurses' role in urinary matters mainly comprised documentation, while the rehabilitation staff focused on making it possible for the patient to be independent in toileting. The nursing staff considered urinary incontinence a common condition for older people and that it was convenient for the patients to have an indwelling catheter or incontinence pad/pant, although they acknowledged some of the risks associated with these procedures. Conclusions: Urinary incontinence is not a priority in orthopaedic care, and urinary incontinence guidelines are not applied. Further, attitudes and actions are mainly characterised by a lack of urinary incontinence knowledge and the nursing and rehabilitation staff do not take a team approach to preventing and managing urinary incontinence. Relevance to clinical practice: An increased focus on knowledge on urinary incontinence and evidence-based guidelines is needed. To secure evidence-based practice, the team of nursing and rehabilitation staff and managers must be aligned and work actively together, also including the patient in the team

A fiber-rich diet and radiation-induced injury in the murine intestinal mucosa

Dietary fiber is considered a strong intestinal protector, but we do not know whether dietary fiber protects against the long-lasting mucosal damage caused by ionizing radiation. To evaluate whether a fiber-rich diet can ameliorate the long-lasting pathophysiological hallmarks of the irradiated mucosa, C57BL/6J mice on a fiber-rich bioprocessed oat bran diet or a fiber-free diet received 32 Gray in four fractions to the distal colorectum using a linear accelerator and continued on the diets for one, six or 18 weeks. We quantified degenerating crypts, crypt fission, cell proliferation, crypt survival, macrophage density and bacterial infiltration. Crypt loss through crypt degeneration only occurred in the irradiated mice. Initially, it was most frequent in the fiber-deprived group but declined to levels similar to the fiber-consuming group by 18 weeks. The fiber-consuming group had a fast response to irradiation, with crypt fission for growth or healing peaking already at one week post-irradiation, while crypt fission in the fiber-deprived group peaked at six weeks. A fiber-rich diet allowed for a more intense crypt cell proliferation, but the recovery of crypts was eventually lost by 18 weeks. Bacterial infiltration was a late phenomenon, evident in the fiber-deprived animals and intensified manyfold after irradiation. Bacterial infiltration also coincided with a specific proinflammatory serum cytokine profile. In contrast, mice on a fiber-rich diet were completely protected from irradiation-induced bacterial infiltration and exhibited a similar serum cytokine profile as sham-irradiated mice on a fiber-rich diet. Our findings provide ample evidence that dietary fiber consumption modifies the onset, timing and intensity of radiation-induced pathophysiological processes in the intestinal mucosa. However, we need more knowledge, not least from clinical studies, before this finding can be introduced to a new and refined clinical practice