The stress response neuropeptide CRF increases amyloid-ß production by regulating γ-secretase activity.

The biological underpinnings linking stress to Alzheimer's disease (AD) risk are poorly understood. We investigated how corticotrophin releasing factor (CRF), a critical stress response mediator, influences amyloid-ß (Aß) production. In cells, CRF treatment increases Aß production and triggers CRF receptor 1 (CRFR1) and γ-secretase internalization. Co-immunoprecipitation studies establish that γ-secretase associates with CRFR1; this is mediated by ß-arrestin binding motifs. Additionally, CRFR1 and γ-secretase co-localize in lipid raft fractions, with increased γ-secretase accumulation upon CRF treatment. CRF treatment also increases γ-secretase activity in vitro, revealing a second, receptor-independent mechanism of action. CRF is the first endogenous neuropeptide that can be shown to directly modulate γ-secretase activity. Unexpectedly, CRFR1 antagonists also increased Aß. These data collectively link CRF to increased Aß through γ-secretase and provide mechanistic insight into how stress may increase AD risk. They also suggest that direct targeting of CRF might be necessary to effectively modulate this pathway for therapeutic benefit in AD, as CRFR1 antagonists increase Aß and in some cases preferentially increase Aß42 via complex effects on γ-secretase.

Maternal Metabolic Complications in Pregnancy and Offspring Behavior Problems at 2 Years of Age.

Objectives Prenatal maternal metabolic problems such as pre-pregnancy adiposity, excess gestational weight gain, and gestational diabetes mellitus (GDM) are associated with an increased risk of psychopathology in offspring. We examined whether these exposures were linked to symptoms of emotional and behavioral problems in offspring at 2 years of age, or if associations were due to confounding variables. Methods Data from 815 mother-child pairs enrolled at the Edmonton site of the Canadian Healthy Infant Longitudinal Development cohort were used to examine associations between gestational metabolic complications and scores on the externalizing and internalizing scales of the Child Behavior Checklist (CBCL-1½ to 5) at age two. Associations between maternal metabolic complications and offspring psychopathology were assessed before and after adjustment for gestational diet, socioeconomic status (SES), postpartum depression (PPD), prenatal smoking and breastfeeding. Results Pre-pregnancy body mass index and GDM, but not gestational weight gain, predicted more offspring externalizing and internalizing problems. However, after adjustment for confounding variables, these associations were no longer statistically significant. Post-hoc analyses revealed that gestational diet accounted for unique variance in both externalizing (semi-partial rdiet = - 0.20, p < 0.001) and internalizing (semi-partial rdiet = - 0.16, p = 0.01) problems. PPD and SES also accounted for a similar amount of variance for both externalizing (semi-partial rPPD = 0.17, p < 0.001; rses = - 0.11, p = 0.03) and internalizing problems (semi-partial rPPD = 0.21, p < 0.001; rses = - 0.14, p = 0.004). Conclusions for Practice Since the confounding effect of gestational diet persisted after adjustment for, and was similar in magnitude to, SES and PPD, future research should consider the impact of unhealthy prenatal diets on offspring neurodevelopment.

Visuospatial Working Memory Capacity Predicts Physiological Arousal in a Narrative Task.

Physiological arousal that occurs during narrative production is thought to reflect emotional processing and cognitive effort (Bar-Haim et al. in Dev Psychobiol 44:238-249, 2004). The purpose of this study was to determine whether individual differences in visuospatial working memory and/or verbal working memory capacity predict physiological arousal in a narrative task. Visuospatial working memory was a significant predictor of skin conductance level (SCL); verbal working memory was not. When visuospatial working memory interference was imposed, visuospatial working memory was no longer a significant predictor of SCL. Visuospatial interference also resulted in a significant reduction in SCL. Furthermore, listener ratings of narrative quality were contingent upon the visuospatial working memory resources of the narrator. Potential implications for educators and clinical practitioners are discussed.

Effects of Perinatal Stroke on Executive Functioning and Mathematics Performance in Children.

The goal of this study was to examine executive functioning, math performance, and visuospatial processing skills of children with perinatal stroke, which have not been well explored in this population. Participants included 18 children with perinatal stroke (aged 6-16 years old) and their primary caregiver. Each child completed standardized tests of executive function and visuospatial processing skills, Intelligence Quotient (IQ), and math achievement. Performance on executive function, IQ, math, and visuospatial processing tests was significantly lower in children with perinatal stroke when compared to normative means. Poorer inhibitory control was associated with worse math performance. Increased age at testing was associated with better performance on visuospatial ability (using standardized scores), and females performed better than males on a test of inhibitory control. Children with perinatal stroke displayed a range of neuropsychological impairments, and difficulties with executive function (inhibition) may contribute to math difficulties in this population.

Learning and memory profiles in youth with perinatal stroke: a study of the Child and Adolescent Memory Profile (ChAMP).

There is limited understanding of the effect of perinatal stroke on child and adolescent learning and memory abilities. This study sought to evaluate the clinical utility of the Child and Adolescent Memory Profile (ChAMP) in quantifying memory performance in youth with perinatal stroke. Children and adolescents aged 6-16 years old with a history of perinatal stroke (PS; n = 41) completed two subtests from the ChAMP (Lists and Objects). Age, sex, and ethnicity-matched healthy control (HC) data were obtained from the test publisher's standardization data set. Participants with a history of PS performed significantly worse (p < .05) with medium effect size (ƞp2 ≥ .06) than HC on the ChAMP Screening Index and on all ChAMP Lists and Objects scaled scores. Classification accuracy for the ChAMP scores ranged from 57% to 68% with the area under the curve ranging from .62-.75. No significant group differences on ChAMP performance (p > .05) were found for stroke side (left versus right-sided) or for seizure history (present versus absent). This study supports the utility of the ChAMP in perinatal stroke patients by demonstrating significantly worse performance in verbal and visual memory than HC. Classification accuracy is limited, but supportive for the Screening Index and Objects Delayed scores. The ChAMP may be a useful tool for evaluating cognition in this population when taken alongside the context of other tests, background history, and clinical observations.

Executive behavior and functional abilities in children with perinatal stroke and the associated caregiver impact.

Perinatal stroke is the most common form of stroke in childhood and is followed by a variety of outcomes, with many children experiencing specific functional and neuropsychological deficits. The association of these outcomes with the psychosocial impact caregivers face is not well documented. The goal of our pilot study was to examine caregivers' perception of executive behavior and functional abilities among children with perinatal stroke, and how these outcomes impact the caregivers. We administered three questionnaires to primary caregivers of children with perinatal stroke to obtain caregiver-reported measures of (1) executive behavior of their child (Behavior Rating Inventory of Executive Function, Second Edition), (2) the functional abilities of their child (Pediatric Evaluation of Disability Inventory Computer Adaptive Test), and (3) the psychosocial impact experienced by the caregiver themselves (Parental Outcome Measure). Participants included 20 children (mean age = 9.3 years, range = 6-16 years) with perinatal stroke and their primary caregivers. Functional abilities in the children were rated as clinically impaired in the domains of daily activities and mobility. Half of the children exhibited clinically impaired ratings on at least one executive behavior domain, but the mean scores for these domains did not reach clinically impaired levels. Greater ratings of problems in daily activities for the child was associated with greater caregiver guilt (r = -0.55, p = 0.02). Caregivers of children with perinatal stroke who experience limitations in performing daily activities should be more closely monitored for adverse impact and be provided the necessary support and education to alleviate the associated guilt.

Chronic pulmonary artery pressure elevation is insufficient to explain right heart failure.

BACKGROUND: The most important determinant of longevity in pulmonary arterial hypertension is right ventricular (RV) function, but in contrast to experimental work elucidating the pathobiology of left ventricular failure, there is a paucity of data on the cellular and molecular mechanisms of RV failure. METHODS AND RESULTS: A mechanical animal model of chronic progressive RV pressure overload (pulmonary artery banding, not associated with structural alterations of the lung circulation) was compared with an established model of angioproliferative pulmonary hypertension associated with fatal RV failure. Isolated RV pressure overload induced RV hypertrophy without failure, whereas in the context of angioproliferative pulmonary hypertension, RV failure developed that was associated with myocardial apoptosis, fibrosis, a decreased RV capillary density, and a decreased vascular endothelial growth factor mRNA and protein expression despite increased nuclear stabilization of hypoxia-induced factor-1alpha. Induction of myocardial nuclear factor E2-related factor 2 and heme-oxygenase 1 with a dietary supplement (Protandim) prevented fibrosis and capillary loss and preserved RV function despite continuing pressure overload. CONCLUSIONS: These data brought into question the commonly held concept that RV failure associated with pulmonary hypertension is due strictly to the increased RV afterload.

Interleukin-1 trap attenuates cardiac remodeling after experimental acute myocardial infarction in mice.

BACKGROUND: Interleukin-1 (IL-1) is an inflammatory cytokine that responds as an acute phase reactant during acute myocardial infarction. Conflicting data describe the role of anti-IL-1 interventions to reduce cardiac remodeling after AMI. IL-1 Trap is a modified recombinant fusion protein that binds circulating IL-1. Our study evaluated the effects of murine IL-1 Trap on cardiac remodeling after AMI resulting from permanent surgical coronary artery ligation. METHODS: Mice received treatment with intraperitoneal injection of murine IL-1 Trap (1 mg/kg [n = 5], 5 mg/kg [n = 5], or 30 mg/kg [n = 5]) or NaCl 0.9% (saline; n = 10) every 48 hours after surgery. Transthoracic echocardiography was performed at baseline and 7 days after surgery. Inhibition of IL-1 signaling was determined by measurement of IL-6 plasma levels (enzyme-linked immunosorbent assay) after IL-1b injection. Apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) was measured in murine heart samples and in a primary culture of murine cardiomyocytes. RESULTS: Mice treated with 5 mg/kg or 30 mg/kg IL-1 Trap had more favorable cardiac remodeling and echocardiographic assessment of infarct size at 7 days compared with saline (P < 0.05 for each comparison). Treatment with IL-1 Trap also reduced apoptosis and IL-6 levels compared with saline treatment. CONCLUSIONS: IL-1 Trap ameliorates cardiac remodeling and reduces cardiomyocyte apoptosis after experimental acute myocardial infarction in the mouse.

Pharmacologic inhibition of phosphoinositide 3-kinase gamma (PI3Kγ) promotes infarct resorption and prevents adverse cardiac remodeling after myocardial infarction in mice.

BACKGROUND: Phosphoinositide 3-kinase gamma is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure. METHODS: CD-1 male mice were randomly assigned to pharmacologic inhibition of phosphoinositide 3-kinase gamma using AS-605240 (10 mg/kg/day intraperitoneally) or vehicle (NaCl 0.9% + DMSO 25% solution) for 14 days after experimental AMI induced by surgical coronary artery ligation. Echocardiography was performed at baseline and 1, 7, 14, and 28 days after surgery to measure left ventricular dimensions and function. Infarct size was also measured at weekly intervals to evaluate for infarct resorption. RESULTS: When compared with vehicle-treated mice over the 4-week period, animals treated with AS-605240 showed a smaller increase in left ventricular cavitary dimensions, a smaller decrease in left ventricular systolic function (P < 0.05), and a significant increase in posterior wall diastolic and systolic thickness reflective of compensatory hypertrophy (P < 0.05). Initial infarct size (measured at 24 hours) was not different comparing AS-605240 (29% ± 4%) and vehicle-treated mice (31% ± 1%, P = nonsignificant). At 4 weeks after AMI, infarct size was significantly smaller in the AS-605240-treated mice (14% ± 2%) compared with vehicle-treated mice (28% ± 3%, P < 0.001), reflecting greater infarct resorption. CONCLUSIONS: Phosphoinositide 3-kinase gamma inhibition with AS-605240 after AMI leads to enhanced infarct resorption, greater compensatory hypertrophy of the nonischemic myocardium, and more favorable cardiac remodeling and function.

Pharmacologic inhibition of myeloid differentiation factor 88 (MyD88) prevents left ventricular dilation and hypertrophy after experimental acute myocardial infarction in the mouse.

BACKGROUND: Myeloid differentiation factor 88 (MyD88) is an endogenous adaptor protein that coordinates the inflammatory response to agonists of the Toll-like receptor and interleukin-1 receptor families. This particular response is activated following myocardial ischemia and infarction and may represent a viable target for pharmacologic inhibition. The current study tested MyD88 inhibitors in a murine model of nonreperfused acute myocardial infarction (AMI). METHODS: AMI was induced by permanent ligation of the left coronary artery. Adult, male, Imprinting Control Region mice were randomized to daily injections with 1 of 2 MyD88 pharmacologic inhibitors (ST2825 25 mg/kg or IMG2005 1 mg/kg), saline, or pretreatment with MyD88-targeted silencing small interfering RNA (siRNA) or scrambled nontargeted siRNA (n = 6 for each group). Echocardiography was performed at baseline and 7 days after surgery to evaluate pathologic cardiac enlargement. RESULTS: Pharmacologic inhibition of MyD88 with ST2825 or IMG2005) and MyD88-targeted siRNA protected against left ventricular (LV) dilatation (reduced LV end-systolic and LV end-diastolic diameter) and hypertrophy. This protection occurred despite no measurable reduction in infarct size. CONCLUSIONS: Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.

BRI2 (ITM2b) inhibits Abeta deposition in vivo.

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid beta precursor protein (APP) genes support the hypothesis that cerebral accumulation of amyloidogenic peptides in familial British and familial Danish dementias and Alzheimer's disease (AD) is associated with neurodegeneration. We have used somatic brain transgenic technology to express the BRI2 and BRI2-Abeta1-40 transgenes in APP mouse models. Expression of BRI2-Abeta1-40 mimics the suppressive effect previously observed using conventional transgenic methods, further validating the somatic brain transgenic methodology. Unexpectedly, we also find that expression of wild-type human BRI2 reduces cerebral Abeta deposition in an AD mouse model. Additional data indicate that the 23 aa peptide, Bri23, released from BRI2 by normal processing, is present in human CSF, inhibits Abeta aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Abeta deposition in vivo.

Abeta40 inhibits amyloid deposition in vivo.

Numerous studies have established a pivotal role for Abeta42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Abeta40 is the predominant form of amyloid beta (Abeta) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in Abeta40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Abeta40 mice that selectively express high levels of Abeta40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Abeta42A mice expressing Abeta42 selectively and analyzed parenchymal and cerebrovascular Abeta deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Abeta40 decreased Abeta deposition by 60-90%. These results demonstrate that Abeta42 and Abeta40 have opposing effects on amyloid deposition: Abeta42 promotes amyloid deposition but Abeta40 inhibits it. In addition, increasing Abeta40 levels protected BRI-Abeta40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Abeta40 with respect to amyloid deposition suggest that strategies that preferentially target Abeta40 may actually worsen the disease course and that selective increases in Abeta40 levels may actually reduce the risk for development of AD.

Parent-Reported Symptoms of Sleep-Disordered Breathing Are Associated With Increased Behavioral Problems at 2 Years of Age: The Canadian Healthy Infant Longitudinal Development Birth Cohort Study.

Study Objectives: To examine the association between the age of onset and duration of parent-reported symptoms of sleep-disordered breathing (SDB) and behavioral problems at age 2. Methods: Parent-reported SDB symptoms were assessed quarterly between 3 months and 2 years among 583 Canadian Healthy Infant Longitudinal Development Edmonton-site participants. Parent-reported SDB symptoms were clustered into phenotypes using group-based trajectory analysis based on age of onset and duration of symptoms. Home-based polysomnography (PSG) was completed at 1 year. The Child Behavior Checklist preschool-version (Mean T-score 50, standard deviation 10 points) assessed total, externalizing (attention), and internalizing (anxiety, depression) behaviors at 2 years. Results: Four phenotypes were identified: no SDB (64.7%), early-onset SDB (15.7%, peak symptoms at 9 months), late-onset (14.2%, peak symptoms at 18 months), and persistent SDB symptoms (5.3%, peak symptoms from 3 through 24 months). Persistent SDB (9.5 points, 95% CI 1.7, 17.2; p = .02) predicted the greatest magnitude of effect of total behavior problems, compared with children without SDB. Children with early-onset SDB (3.5 points, 95% CI 1.6, 5.4; p ≤ .001) and late-onset SDB (6.1 points 95% CI 4.0, 8.3; p ≤ .001) had increased total behavioral problems than children without SDB to 2 years. Additional analyses showed that the SDB phenotypes' trajectories were important for internalizing but not for externalizing behavior problems. There were no significant associations between home-PSG and parent-reported behavior problems. Conclusions: Findings suggest that the age of onset and duration of parent-reported SDB symptoms prior to age 2 have adverse consequences for overall behavior problems.

Shorter sleep duration is associated with reduced cognitive development at two years of age.

BACKGROUND: Both short sleep duration and sleep-disordered breathing (SDB) are associated with poor neurocognitive development. However, the co-contributions of short sleep duration and SDB on neurodevelopment in pre-school children are relatively unknown. METHODS: We assessed both sleep duration and SDB by quarterly questionnaire from three months to two years of age among Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort participants. Group-based modeling determined trajectories of total, daytime, and nighttime sleep duration and SDB. Linear regression was used to assess the impact of sleep duration and SDB trajectories on cognitive (primary outcome) and language (secondary) development at two years of age as assessed by the Bayley Scale of Infant Development (BSID-III) (mean 100; standard deviation of 15). RESULTS: Of the 822 CHILD Edmonton participants, 703 (86%) were still enrolled at two years of age with 593 having BSID-III data at two years of age. Trajectory analysis identified four total sleep durations phenotypes [short sleepers (17.9%), decline to short sleepers (21.1%), intermediate sleepers (36.9%) and long sleepers (24.1%)]. Compared to children with intermediate sleep durations, short sleepers had a 5.2-point lower cognitive development score at two years of age [standard error (SE) 1.7; p = 0.002]. Nocturnal sleep duration, compared to daytime sleep duration had the greatest effect on cognitive development. We also identified three SDB symptom trajectories [early-onset SDB (15.7%), late-onset SDB (14.2%), and persistent SDB (5.3%)] and 79.5% of children had no SDB symptoms. Children with persistent SDB also had a 5.3-point lower language score (SE 2.7; p = 0.05) compared to children with no SDB. SDB trajectories were not associated with cognitive development. CONCLUSION: In a population-representative birth cohort study, both short sleep duration and SDB were associated with adverse neurodevelopment at two years of age. Children with short nighttime sleep duration had lowered cognitive and language scores and children with persistent SDB also had lower language scores.

Phenotypes of sleep-disordered breathing symptoms to two years of age based on age of onset and duration of symptoms.

OBJECTIVE: Childhood sleep-disordered breathing (SDB) symptoms may comprise multiple phenotypes depending on craniofacial anatomy, tonsil and adenoid growth, body habitus, and rhinitis symptoms. The primary objective of this study is to identify and characterize the different SDB phenotypes to two years of age. METHODS: Data from 770 infants in the Edmonton sub-cohort of the Canadian Healthy Infant Longitudinal Study (CHILD) were analyzed to identify SDB phenotypes based on age of onset and duration of symptoms. Parents completed the 22-item sleep-related breathing disorder (SRBD) scale. Children with a SRBD ratio greater than 0.33 were considered positive for SDB at each quarterly assessment between three months and two years. The STATA Proc trajectory extension identified SDB phenotypes based on their age of onset and duration of symptoms and attributed the percentage chance of a participant being assigned to each phenotype. Multivariate linear regression identified factors associated with increased risk of being assigned to each SDB phenotype. RESULTS: Trajectory analysis identified four phenotypes: no SDB (65.7%), early-onset SDB (15.7%) with peak symptoms at nine months, late-onset SDB (14.2%) with peak symptoms at 18 months, and persistent SDB (5.3%) with symptoms from 3 to 24 months. Rhinitis was associated with all three SDB symptom trajectories (p < 0.05). Children with gastroesophageal reflux disease presented with early (p = 0.03) and late SDB (p < 0.001). Maternal obstructive sleep apnea syndrome (OSAS) was associated with persistent (p = 0.01) and late SDB (p < 0.001). Atopy (positive skin prick test at one year) was associated with persistent SDB (p = 0.04). Infants born prior to 36.5 weeks gestational age were more likely to present with late SDB (p = 0.03). CONCLUSION: Childhood SDB symptoms, rather than being a homogenous disorder, may comprise multiple overlapping phenotypes each with unique risk factors.

Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice.

Accumulation of amyloid beta protein (Abeta) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Abeta are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Abeta single-chain variable fragments (scFvs) as a potentially safer form of anti-Abeta immunotherapy. We have generated and characterized three anti-Abeta scFvs that recognize Abeta 1-16, Abeta x-40, or Abeta x-42. To achieve widespread brain delivery, constructs expressing these anti-Abeta scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-Abeta scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Abeta deposition by 25-50%. These data suggest that intracranial anti-Abeta scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a "somatic brain transgenic" paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.

Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models.

A number of hypotheses regarding how anti-Abeta antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Abeta immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Abeta levels after a single peripheral dose of anti-Abeta antibodies to both wild-type (WT) and young non-Abeta depositing APP and BRI-Abeta42 mice. The rapid rise in plasma Abeta observed after antibody (Ab) administration is attributable to prolongation of the half-life of Abeta bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Abeta, we find no evidence that total brain Abeta levels are significantly altered. Surprisingly, cerebral spinal fluid Abeta levels transiently rise, and when Ab:Abeta complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Abeta, these data provide a framework to evaluate proposed mechanisms of Abeta attenuation mediated by peripheral administration of an anti-Abeta monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Abeta or targeting a low abundance aggregation intermediate.

A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.

The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.

Interleukin-1 receptor 1 knockout has no effect on amyloid deposition in Tg2576 mice and does not alter efficacy following Abeta immunotherapy.

BACKGROUND: Microglial activation has been proposed to facilitate clearance of amyloid beta protein (Abeta) from the brain following Abeta immunotherapy in amyloid precursor protein (APP) transgenic mice. Interleukin-1 receptor 1 knockout (IL-1 R1-/-) mice are reported to exhibit blunted inflammatory responses to injury. To further define the role of IL-1-mediated inflammatory responses and microglial activation in this paradigm, we examined the efficacy of passive Abeta immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Abeta deposition in the absence of additional manipulations. METHODS: We passively immunized Tg2576 mice crossed into the IL-1 R1-/- background (APP/IL-1 R1-/- mice) with an anti-Abeta1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Abeta deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Abeta deposition in untreated mice. Biochemical and immunohistochemical Abeta loads and microglial activation was assessed. RESULTS: Passive immunization with anti-Abeta mAb was effective in reducing plaque load in APP/IL-1 R1-/- mice when the immunization was started prior to significant plaque deposition. Similar to previous studies, immunization was not effective in older APP/IL-1 R1-/- mice or IL-1 R1 sufficient wild type Tg2576 mice. Our analysis of Abeta deposition in the untreated APP/IL-1 R1-/- mice did not show differences on biochemical Abeta loads during normal aging of these mice compared to IL-1 R1 sufficient wild type Tg2576 mice. CONCLUSION: We find no evidence that the lack of the IL-1 R1 receptor influences either Abeta deposition or the efficacy of passive immunotherapy. Such results are consistent with other studies in Tg2576 mice that suggest microglial activation may not be required for efficacy in passive immunization approaches.

Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model.

In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p<0.05). Consistent with this, we found 30% higher learning Performance index (PI) scores in Drosophila offspring from parents who consumed 30% fruit juice supplementation prenatally (PI: 85.7; SE 1.8; p<0.05) compared to the offspring of standard diet parents (PI: 65.0 SE 3.4). Using the Drosophila model, we also show that the cyclic adenylate monophosphate (cAMP) pathway may be a major regulator of this effect, as prenatal fruit associated cognitive enhancement was blocked in Drosophila rutabaga mutants with reduced Ca(2+)-Calmodulin-dependent adenylyl cyclase. Moreover, gestation is a critical time for this effect as postnatal fruit intake did not enhance cognitive performance in either humans or Drosophila. Our study supports increased fruit consumption during pregnancy with significant increases in infant cognitive performance. Validation in Drosophila helps control for potential participant bias or unmeasured confounders.