Intracranial injection of AAV expressing NEP but not IDE reduces amyloid pathology in APP+PS1 transgenic mice

The accumulation of β-amyloid peptides in the brain has been recognized as an essential factor in Alzheimer\u27s disease pathology. Several proteases, including Neprilysin (NEP), endothelin converting enzyme (ECE), and insulin degrading enzyme (IDE), have been shown to cleave β-amyloid peptides (Aβ). We have previously reported reductions in amyloid in APP+PS1 mice with increased expression of ECE. In this study we compared the vector-induced increased expression of NEP and IDE. We used recombinant adeno-associated viral vectors expressing either native forms of NEP (NEP-n) or IDE (IDE-n), or engineered secreted forms of NEP (NEP-s) or IDE (IDE-s). In a six-week study, immunohistochemistry staining for total Aβ was significantly decreased in animals receiving the NEP-n and NEP-s but not for IDE-n or IDE-s in either the hippocampus or cortex. Congo red staining followed a similar trend revealing significant decreases in the hippocampus and the cortex for NEP-n and NEP-s treatment groups. Our results indicate that while rAAV-IDE does not have the same therapeutic potential as rAAV-NEP, rAAV-NEP-s and NEP-n are effective at reducing amyloid loads, and both of these vectors continue to have significant effects nine months post-injection. As such, they may be considered reasonable candidates for gene therapy trials in AD

Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition

INTRODUCTION: Tau pathology is associated with a number of age-related neurodegenerative disorders. Few treatments have been demonstrated to diminish the impact of tau pathology in mouse models and none are yet effective in humans. Histone deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from cytoplasmic proteins, rather than nuclear histones. Its substrates include tubulin, heat shock protein 90 and cortactin. Tubastatin A is a selective inhibitor of HDAC6. Modification of tau pathology by specific inhibition of HDAC6 presents a potential therapeutic approach in tauopathy. METHODS: We treated rTg4510 mouse models of tau deposition and non-transgenic mice with tubastatin (25 mg/kg) or saline (0.9%) from 5 to 7 months of age. Cognitive behavior analysis, histology and biochemical analysis were applied to access the effect of tubastatin on memory, tau pathology and neurodegeneration (hippocampal volume). RESULTS: We present data showing that tubastatin restored memory function in rTg4510 mice and reversed a hyperactivity phenotype. We further found that tubastatin reduced the levels of total tau, both histologically and by western analysis. Reduction in total tau levels was positively correlated with memory improvement in these mice. However, there was no impact on phosphorylated forms of tau, either by histology or western analysis, nor was there an impact on silver positive inclusions histologically. CONCLUSION: Potential mechanisms by which HDAC6 inhibitors might benefit the rTg4510 mouse include stabilization of microtubules secondary to increased tubulin acetylation, increased degradation of tau secondary to increased acetylation of HSP90 or both. These data support the use of HDAC6 inhibitors as potential therapeutic agents against tau pathology

CCL2 Overexpression in the Brain Promotes Glial Activation and Accelerates Tau Pathology in a Mouse Model of Tauopathy

Innate immune activation is a major contributor to Alzheimer’s Disease (AD) pathophysiology, although the mechanisms involved are poorly understood. Chemokine C-C motif ligand (CCL) 2 is produced by neurons and glial cells and is upregulated in the AD brain. Transgene expression of CCL2 in mouse models of amyloidosis produces microglia-induced amyloid β oligomerization, a strong indication of the role of these activation pathways in the amyloidogenic processes of AD. We have previously shown that CCL2 polarizes microglia in wild type mice. However, how CCL2 signaling contributes to tau pathogenesis remains unknown. To address this question, CCL2 was delivered via recombinant adeno-associated virus serotype 9 into both cortex and hippocampus of a mouse model with tau pathology (rTg4510). We report that CCL2 overexpression aggravated tau pathology in rTg4510 as shown by the increase in Gallyas stained neurofibrillary tangles as well as phosphorylated tau-positive inclusions. In addition, biochemical analysis showed a reduction in the levels of detergent-soluble tau species followed by increase in the insoluble fraction, indicating a shift toward larger tau aggregates. Indeed, increased levels of high molecular weight species of phosphorylated tau were found in the mice injected with CCL2. We also report that worsening of tau pathology following CCL2 overexpression was accompanied by a distinct inflammatory response. We report an increase in leukocyte common antigen (CD45) and Cluster of differentiation 68 (CD68) expression in the brain of rTg4510 mice without altering the expression levels of a cell-surface protein Transmembrane Protein 119 (Tmem119) and ionized calcium-binding adaptor molecule 1 (Iba-1) in resident microglia. Furthermore, the analysis of cytokines in brain extract showed a significant increase in interleukin (IL)-6 and CCL3, while CCL5 levels were decreased in CCL2 mice. No changes were observed in IL-1α, IL-1β, TNF-α. IL-4, Vascular endothelial growth factor-VEGF, IL-13 and CCL11. Taken together our data report for the first time that overexpression of CCL2 promotes the increase of pathogenic tau species and is associated with glial neuroinflammatory changes that are deleterious. We propose that these events may contribute to the pathogenesis of Alzheimer’s disease and other tauopathies

Erratum: Corrigendum: Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution

International Chicken Genome Sequencing Consortium. The Original Article was published on 09 December 2004. Nature432, 695–716 (2004). In Table 5 of this Article, the last four values listed in the ‘Copy number’ column were incorrect. These should be: LTR elements, 30,000; DNA transposons, 20,000; simple repeats, 140,000; and satellites, 4,000. These errors do not affect any of the conclusions in our paper. Additional information. The online version of the original article can be found at 10.1038/nature0315

La préparation professionnelle de l’enseignant et la formation universitaire américaine : un partenariat trouble, un avenir prometteur

Teacher education in the state of Maine (USA) is founded on shared roles between university preparation and professional preparation, the latter situated in the university. Both disciplinary knowledge and pedagogical knowledge are thus in play. We offer a brief review of the global structure of teacher education in Maine, in particular as it has evolved at the University of Maine-Farmington. We then present specific examples of teacher education curriculum, showing faculty roles from the College of Education and the College of Arts and Sciences, both shared and separate. We then explore some resulting tensions, indicative of the broader complications in the relationship between these two domains of knowledge and preparation. Finally, we explore initiatives addressing these relationships, including shared faculty positions, curricular initiatives, and collaborative research and assessment projects, and outline future paths to pursue.La formation des maîtres dans l’État du Maine aux USA est fondée sur un travail partagé entre deux types de structures bien séparées au sein de la même université. L’une des structures est consacrée à l’enseignement des disciplines, l’autre à la préparation professionnelle et aux savoirs pédago-didactiques que celle-ci requiert. L’intégration de ces deux volets d’études dans la même université n’empêche pas des tensions dans la collaboration relative au déroulement des curricula et de l’ensemble des préparations professionnelles. Diverses initiatives sont prises pour tenter de les résorber ou de les atténuer.Berger Rebecca, Nash Marcia, Overstreet Deborah, Eason Grace, Donahue Christiane. La préparation professionnelle de l’enseignant et la formation universitaire américaine : un partenariat trouble, un avenir prometteur. In: Spirale. Revue de recherches en éducation, n°46, 2010. Formations des enseignants, sous la direction de Guy Legrand et Dominique-Guy Brassart. pp. 109-122

The role of health literacy and communication habits on previous colorectal cancer screening among low-income and uninsured patients

Objective: To determine the association between health literacy, communication habits and colorectal cancer (CRC) screening among low-income patients. Methods: Survey responses of patients who received financial assistance for colonoscopy between 2011 and 2014 at a family medicine residency clinic were analyzed using multivariate logistic regression (n = 456). There were two dependent variables: (1) previous CRC screening and (2) CRC screening adherence. Our independent variables of interest were health literacy and communication habits. Results: Over two-thirds (67.13%) of respondents had not been previously screened for CRC. Multivariate analysis showed a decreased likelihood of previous CRC screening among those who had marginal (OR = 0.52; 95% CI = 0.29–0.92) or inadequate health literacy (OR = 0.49; 95% CI = 0.27–0.87) compared to those with adequate health literacy. Controlling for health literacy, the significant association between educational attainment and previous CRC screening was eliminated. Thus, health literacy mediated the relationship between educational attainment and previous CRC screening. There was no significant association between communication habits and previous CRC screening. There was no significant association between screening guideline adherence, and health literacy or communication. Conclusion: Limited health literacy is a potential barrier to CRC screening. Suboptimal CRC screening rates reported among those with lower educational attainment may be mediated by limited health literacy

Study 2: Congophilic staining is observed in mice throughout both ipsilateral hippocampus (A, B and C) and ipsilateral anterior cortex (D, E and F).

<p>Congophilic staining in the hippocampus of animals that received intracranial injections of rAAV- IDE-n (B) or IDE-s (C) is unchanged compared to staining in those animals that received injections of control vector rAAV- GFP (A). Congophilic staining in the anterior cortex of mice that received intracranial injections of rAAV- IDE-n (E) or NEP-s (F) is also unchanged compared to staining in mice that received control vector rAAV- GFP(D). Scale bar = 200 µm. Quantification of percent area of positive total congophilic staining is shown in G and H (hemisphere ipsilateral to injection sites). No significant differences were found. n = 8/group.</p

Study 3: CD68 (A-C) and CD45 (D-F) immunostaining is observed throughout the hippocampus of study mice.

<p>In the hippocampus, no significant differences are observed in the amount of total CD68 staining between the NEP-n, NEP-s, and NEP-m groups, but CD45 staining in NEP-s treated mice is greater than CD45 staining in NEP-m treated mice. Scale bar = 50 µm. Panels G and H present ANOVA analysis of the ratio of CD68 to congophilic staining, and of the ratio of quantitated CD45 to congophilic staining, respectively, in the hippocampus of study mice. The (*) indicates significance compared to NEP-m mice with p<0.05, and the (^∧) indicates significance compared to Tg control mice with p<0.05 or p<0.01 (°).Tg control (n = 9), NEP-n (n = 4), NEP-m (n = 7), NEP-s (n = 6).</p