Coronin 1C harbours a second actin-binding site that confers co-operative binding to F-actin

Dynamic rearrangement of actin filament networks is critical for cell motility, phagocytosis and endocytosis. Coronins facilitate these processes, in part, by their ability to bind F-actin (filamentous actin). We previously identified a conserved surface-exposed arginine (Arg30) in the β-propeller of Coronin 1B required for F-actin binding in vitro and in vivo. However, whether this finding translates to other coronins has not been well defined. Using quantitative actin-binding assays, we show that mutating the equivalent residue abolishes F-actin binding in Coronin 1A, but not Coronin 1C. By mutagenesis and biochemical competition, we have identified a second actin-binding site in the unique region of Coronin 1C. Interestingly, leading-edge localization of Coronin 1C in fibroblasts requires the conserved site in the β-propeller, but not the site in the unique region. Furthermore, in contrast with Coronin 1A and Coronin 1B, Coronin 1C displays highly co-operative binding to actin filaments. In the present study, we highlight a novel mode of coronin regulation, which has implications for how coronins orchestrate cytoskeletal dynamics

Disruption of arterial perivascular drainage of amyloid-β from the brains of mice expressing the human APOE ε4 allele

Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ40. Aβ40 aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature

Review: Astrocytes in Alzheimer's disease and other age-associated dementias; a supporting player with a central role.

Astrocytes have essential roles in the central nervous system and are also implicated in the pathogenesis of neurodegenerative disease. Forming non-overlapping domains, astrocytes are highly complex cells. Immunohistochemistry to a variety of proteins can be used to study astrocytes in tissue, labelling different cellular components and subpopulations, including GFAP, ALDH1L1, CD44, NDRG2 and amino acid transporters, but none of these label the entire astrocyte population. Increasing heterogeneity is recognised in the astrocyte population, a complexity that is relevant both to their normal function and pathogenic roles. They are involved in neuronal support, as active components of the tripartite synapse and in cell interactions within the neurovascular unit, where they are essential for blood brain barrier maintenance and neurovascular coupling. Astrocytes change with age, and their responses may modulate the cellular effects of neurodegenerative pathologies, which alone do not explain all of the variance in statistical models of neurodegenerative dementias. Astrocytes respond to both the neurofibrillary tangles and plaques of Alzheimer's disease, to hyperphosphorylated tau and Aβ, eliciting an effect which may be neuroprotective or deleterious. Astrocyte hypertrophy, in the form of gliosis, occurs, but also astrocyte injury and atrophy. Loss of normal astrocyte functions may contribute to reduced support for neurons and dysfunction of the neurovascular unit. Understanding how astrocytes contribute to dementia requires an understanding of the underlying heterogeneity of astrocyte populations, and the complexity of their responses to pathology. Enhancing the supportive and neuroprotective components of the astrocyte response has potential translational applications in therapeutic approaches to dementia. This article is protected by copyright. All rights reserved

Falls in young, middle-aged and older community dwelling adults: perceived cause, environmental factors and injury

BACKGROUND: Falls in older people have been characterized extensively in the literature, however little has been reported regarding falls in middle-aged and younger adults. The objective of this paper is to describe the perceived cause, environmental influences and resultant injuries of falls in 1497 young (20–45 years), middle-aged (46–65 years) and older (> 65 years) men and women from the Baltimore Longitudinal Study on Aging. METHODS: A descriptive study where participants completed a fall history questionnaire describing the circumstances surrounding falls in the previous two years. RESULTS: The reporting of falls increased with age from 18% in young, to 21% in middle-aged and 35% in older adults, with higher rates in women than men. Ambulation was cited as the cause of the fall most frequently in all gender and age groups. Our population reported a higher percentage of injuries (70.5%) than previous studies. The young group reported injuries most frequently to wrist/hand, knees and ankles; the middle-aged to their knees and the older group to their head and knees. Women reported a higher percentage of injuries in all age groups. CONCLUSION: This is the first study to compare falls in young, middle and older aged men and women. Significant differences were found between the three age groups with respect to number of falls, activities engaged in prior to falling, perceived causes of the fall and where they fell

Cyclo-oxygenase-2 selective inhibitors and nonsteroidal anti-inflammatory drugs: balancing gastrointestinal and cardiovascular risk

<p>Abstract</p> <p>Background</p> <p>Differences between gastrointestinal and cardiovascular effects of traditional NSAID or cyclooxygenase-2 selective inhibitor (coxib) are affected by drug, dose, duration, outcome definition, and patient gastrointestinal and cardiovascular risk factors. We calculated the absolute risk for each effect.</p> <p>Methods</p> <p>We sought studies with large amounts of information to calculate annualised rates for clearly defined gastrointestinal (complicated upper gastrointestinal perforations, ulcers, or bleeds, but not symptomatic or endoscopic ulcers) and serious cardiovascular outcomes (antiplatelet trial collaborators – APTC – outcome of fatal or nonfatal myocardial infarction or stroke, or vascular death).</p> <p>Results</p> <p>Meta-analyses and large randomised trials specifically analysing serious gastrointestinal bleeding or cardiovascular events occurring with five different coxibs had appropriate data. In total there were 439 complicated upper gastrointestinal events in 49,006 patient years of exposure and 948 serious cardiovascular events in 99,400 patient years of exposure. Complicated gastrointestinal events occurred less frequently with coxibs than NSAIDs; serious cardiovascular events occurred at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events. In the overall comparison, for every 1000 patients treated for a year with coxib rather than NSAID, there would be eight fewer complicated upper gastrointestinal events, but one more fatal or nonfatal heart attack or stroke. Three coxib-NSAID comparisons had sufficient numbers of events for individual comparisons. For every 1000 patients treated for a year with celecoxib rather than an NSAID there would be 12 fewer upper gastrointestinal complications, and two fewer fatal or nonfatal heart attacks or strokes. For rofecoxib there would be six fewer upper gastrointestinal complications, but three more fatal or nonfatal heart attacks or strokes. For lumiracoxib there would be eight fewer upper gastrointestinal complications, but one more fatal or nonfatal heart attack or stroke.</p> <p>Conclusion</p> <p>Calculating annualised event rates for gastrointestinal and cardiovascular harm shows that while complicated gastrointestinal events occur more frequently with NSAIDs than coxibs, serious cardiovascular events occur at approximately equal rates. For each coxib, the reduction in complicated upper gastrointestinal events was numerically greater than any increase in APTC events.</p

Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice

Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer’s disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood–brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice