MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Introduction: Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides.

Methods: We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ, the pathogenic self-aggregating species of Aβ.

Results: MEDI1814 reduces free Aβ without impacting Aβ in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration.

The contrasting role of technology as both supportive and hindering in the everyday lives of people with mild cognitive deficits: a focus group study.

Background: It is well known that people with mild cognitive deficits face challenges when performing complex everyday activities, and that the use of technology has become increasingly interwoven with everyday activities. However, less is known of how technology might be involved, either as a support or hindrance, in different areas of everyday life and of the environments where challenges appear. The aim of this study was to investigate the areas of concern where persons with cognitive deficits meet challenges in everyday life, in what environments these challenges appear and how technology might be involved as part of the challenge and/or the solution to the challenge.

A Disintegrin and A Metalloproteinase-9 (ADAM9): A Novel Proteinase Culprit with Multifarious Contributions to COPD.

Introduction: Proteinases with a disintegrin and a metalloproteinase domain (ADAMs) have not been well studied in COPD. We investigated whether ADAM9 is linked to COPD in humans and mice.

Methods: ADAM9 blood and lung levels were measured in COPD patients versus controls, and air- versus cigarette smoke (CS)-exposed wild-type (WT) mice.

Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis.

Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity.

How older adults with mild cognitive impairment relate to technology as part of present and future everyday life: a qualitative study.

Background: Existing everyday technology as well as potential future technology may offer both challenges and possibilities in the everyday occupations of persons with cognitive decline. To meet their wishes and needs, the perspective of the persons themselves is an important starting point in intervention planning involving technology. The aim of this study was to explore how persons with mild cognitive impairment relate to technology as a part of and as potential support in everyday life - both present and future.

Co-Designing Ambient Assisted Living (AAL) Environments: Unravelling the Situated Context of Informal Dementia Care.

Ambient assisted living (AAL) aims to help older persons "age-in-place" and manage everyday activities using intelligent and pervasive computing technology. AAL research, however, has yet to explore how AAL might support or collaborate with informal care partners (ICPs), such as relatives and friends, who play important roles in the lives and care of persons with dementia (PwDs). In a multiphase codesign process with six (6) ICPs, we envisioned how AAL could be situated to complement their care.

Experienced usability of assistive technology for cognitive support with respect to user goals.

Background: Studies have shown that Assistive Technology (AT) for cognitive support can support users in everyday activities. However, whether the AT actually supports the user to achieve their individual goals must further be examined.

Objective: The study objective was to examine the experienced usability of features in AT for cognitive support for users with cognitive impairment.

Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1.

The role of exosomes in cancer can be inferred from the observation that they transfer tumor cell derived genetic material and signaling proteins, resulting in e.g. increased tumor angiogenesis and metastasis.

Significant junctures on the way towards becoming a user of assistive technology in Alzheimer's disease.

Objective: The aim of this study was to describe how persons in the early stages of Alzheimer's disease (AD) became users of assistive technology (AT), and what the use of AT came to mean to these users and, when relevant, their significant others.

Methods: Persons with AD were provided with individually chosen AT during a six-month period. Semi-structured interviews were conducted during the intervention period.

Glial cell line-derived neurotrophic factor partially ameliorates motor symptoms without slowing neurodegeneration in mice with respiratory chain-deficient dopamine neurons.

Degeneration of midbrain dopamine neurons causes the striatal dopamine deficiency responsible for the hallmark motor symptoms of Parkinson's disease (PD). Intraparenchymal delivery of neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), is a possible future therapeutic approach. In animal PD models, GDNF can both ameliorate neurodegeneration and promote recovery of the dopamine system following a toxic insult.

Computer-based assistive technology and changes in daily living after stroke.

Unlabelled: The aim of this study was to examine in depth how computer-based assistive technology (AT) for cognitive support influenced the everyday lives of both persons who had had a stroke and their significant others.

Method: Four participants, who had experienced cognitive limitations after a stroke, and their significant others were included in the study. The study included an intervention with a specific type of computer-based AT that was installed in the homes of the four participants for a 6-month period.

Adh1 and Adh1/4 knockout mice as possible rodent models for presymptomatic Parkinson's disease.

Alcohol dehydrogenases (ADH) catalyze the reversible metabolism of many types of alcohols and aldehydes to prevent the possible toxic accumulation of these compounds. ADHs are of interest in Parkinson's disease (PD) since these compounds can be harmful to dopamine (DA) neurons. Genetic variants in ADH1C and ADH4 have been found to associate with PD and lack of Adh4 gene activity in a mouse model has recently been reported to induce changes in the DA system.

Modeling Parkinson's disease genetics: altered function of the dopamine system in Adh4 knockout mice.

Class IV alcohol dehydrogenase (ADH4) efficiently reduces aldehydes produced during lipid peroxidation, and may thus serve to protect from toxic effects of aldehydes e.g. on neurons.

Chronic A2A antagonist treatment alleviates parkinsonian locomotor deficiency in MitoPark mice.

Adenosine A(2A) receptor (A(2A)R) antagonists are being investigated as promising treatment strategy for Parkinson's disease (PD). To test whether A(2A)R antagonists are beneficial in early PD stages we used MitoPark mice, a genetic model with gradual degeneration of DA cells. Daily treatment of young MitoPark mice for eight weeks with the A(2A)R antagonist MSX-3 prevented the reduction of spontaneous locomotor activity observed in saline or L-DOPA treated animals.

Design of an optimized scaffold for affibody molecules.

Affibody molecules are non-immunoglobulin-derived affinity proteins based on a three-helical bundle protein domain. Here, we describe the design process of an optimized Affibody molecule scaffold with improved properties and a surface distinctly different from that of the parental scaffold. The improvement was achieved by applying an iterative process of amino acid substitutions in the context of the human epidermal growth factor receptor 2 (HER2)-specific Affibody molecule Z(HER2:342).

Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons.

Transcription factors involved in the specification and differentiation of neurons often continue to be expressed in the adult brain, but remarkably little is known about their late functions. Nurr1, one such transcription factor, is essential for early differentiation of midbrain dopamine (mDA) neurons but continues to be expressed into adulthood. In Parkinson's disease, Nurr1 expression is diminished and mutations in the Nurr1 gene have been identified in rare cases of disease; however, the significance of these observations remains unclear.

Lrrk2 and alpha-synuclein are co-regulated in rodent striatum.

LRRK2, alpha-synuclein, UCH-L1 and DJ-1 are implicated in the etiology of Parkinson's disease. We show for the first time that increase in striatal alpha-synuclein levels induce increased Lrrk2 mRNA levels while Dj-1 and Uch-L1 are unchanged. We also demonstrate that a mouse strain lacking the dopamine signaling molecule DARPP-32 has significantly reduced levels of both Lrrk2 and alpha-synuclein, while mice carrying a disabling mutation of the DARPP-32 phosphorylation site T34A or lack alpha-synuclein do not show any changes.

Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons.

Mitochondrial dysfunction is implicated in the pathophysiology of Parkinson's disease (PD), a common age-associated neurodegenerative disease characterized by intraneuronal inclusions (Lewy bodies) and progressive degeneration of the nigrostriatal dopamine (DA) system. It has recently been demonstrated that midbrain DA neurons of PD patients and elderly humans contain high levels of somatic mtDNA mutations, which may impair respiratory chain function. However, clinical studies have not established whether the respiratory chain deficiency is a primary abnormality leading to inclusion formation and DA neuron death, or whether generalized metabolic abnormalities within the degenerating DA neurons cause secondary damage to mitochondria.

Expression of genes involved in oxidative stress responses in airway epithelial cells of smokers with chronic obstructive pulmonary disease.

Rationale: The molecular mechanisms involved in airway oxidative stress responses reported in healthy smokers and in those with chronic obstructive pulmonary disease (COPD) are poorly understood.

Objectives: To assess the expression of genes involved in oxidative stress responses in the bronchial epithelium of smokers with or without COPD and in relation to disease severity.

Methods: Global gene expression was assessed in bronchial brushings in 38 subjects with COPD, 14 healthy nonsmokers, and 18 healthy smokers.

LRRK2 expression linked to dopamine-innervated areas.

Objective: Leucine-rich repeat kinase 2 (LRRK2) has been linked to Parkinson's disease. Our study explores the expression of LRRK2 in human and rodent brain tissue.

Methods: We analyzed LRRK2 gene activity at the cellular level using in situ hybridization.

Increased phencyclidine-induced hyperactivity following cortical cholinergic denervation.

Altered cholinergic function is considered as a potential contributing factor in the pathogenesis of schizophrenia. We hypothesize that cortical cholinergic denervation may result in changes in glutamatergic activity. Therefore, we lesioned the cholinergic corticopetal projections by local infusion of 192 IgG-saporin into the nucleus basalis magnocellularis of rats.

Glial and neuronal connexin expression patterns in the rat spinal cord during development and following injury.

Spinal cord injury induces a complex cascade of degenerative and remodeling events evolving over time. The possible roles of changed intercellular communication via gap junctions after spinal cord injury (SCI) have remained relatively unexplored. We investigated the temporospatial expression patterns of gap junctional genes and proteins, connexin 43 (Cx43), Cx36, and Cx32, by in situ hybridization and immunohistochemistry in the rat neonatal, adult normal, and adult injured spinal cord.

Nurr1 regulates dopamine synthesis and storage in MN9D dopamine cells.

Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cells during embryonic development. Nurr1 continues to be expressed in adult DA neurons but the role for Nurr1 in inducing and regulating basic dopaminergic functions such as dopamine synthesis and storage has remained unknown. We have previously used MN9D dopamine cells to analyze the role of Nurr1 and retinoids in DA cell maturation.

Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles.

We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3' untranslated region of TH. An frt-flanked neomycin-resistance (neo(r)) cassette was placed in the 3' end of the targeting constructs.

Neurotrophic properties of olfactory ensheathing glia.

Olfactory ensheathing cells (OEC) constitute a specialized population of glia that accompany primary olfactory axons and have been reported to facilitate axonal regeneration after spinal cord injury in vivo. In the present report we describe OEC neurotrophic factor expression and neurotrophic properties of OECs in vitro. Investigation of the rat olfactory system during development and adulthood by radioactive in situ hybridization revealed positive labeling in the olfactory nerve layer for the neurotrophic molecules S-100beta, CNTF, BMP-7/OP-1, and artemin, as well as for the neurotrophic factor receptors RET and TrkC.