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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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, ). 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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate receptive vocabulary achievement among French–English bilinguals in Canada. Standardized test scores of receptive vocabulary were measured in both languages from preschool, early-elementary, and late-elementary French–English bilingual children, and French–English bilingual adults. Mean vocabulary scores across all bilingual age groups were statistically equivalent to or above the standard mean in French and English with the exception of the early-elementary bilinguals who scored below the standard mean on the English vocabulary assessment. Mean vocabulary scores of the preschool and adult bilingual groups were not significantly different from those of their monolingual peers in either language. However, early-elementary and late-elementary bilingual children scored significantly lower than monolinguals on the English vocabulary assessment. The positive sociocultural context for French–English bilingualism in Canada as well as language input changes in school are discussed as underlying reasons for these findings. [ABSTRACT FROM PUBLISHER]

Researchers have speculated that gesture use may be linked to working memory capacity. The purpose of this study was to determine whether the architectures of working memory differ among monolinguals and bilinguals, and to investigate whether individual differences in working memory predict gesture use. Participants relayed a narrative and their gesture production was assessed. Working memory capacity was tested using the Automated Working Memory Assessment (Alloway, 2007). The results provide evidence for different working memory architectures among monolinguals and bilinguals. Additionally, verbal memory significantly predicted iconic gesture use in both language groups, although in slightly different ways. These results are discussed with respect to the functional roles that working memory and gestures serve among monolingual and bilingual populations. [ABSTRACT FROM PUBLISHER]

Background: Microglial activation has been proposed to facilitate clearance of amyloid β protein (Aβ) from the brain following Aβ 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 Aβ immunotherapy in Tg2576 mice crossed into the IL-1 R1-/- background. In addition, we examined if loss of IL-1 R1-/- modifies Aβ 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-Aβ1-16 mAb (mAb9, IgG2a) that we previously showed could attenuate Aβ deposition in Tg2576 mice. We also examined whether the IL-1 R1 knockout background modifies Aβ deposition in untreated mice. Biochemical and immunohistochemical Aβ loads and microglial activation was assessed. Results: Passive immunization with anti-Aβ 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 Aβ deposition in the untreated APP/IL-1 R1-/- mice did not show differences on biochemical Aβ 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 Aβ 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. [ABSTRACT FROM AUTHOR]

In experimental tasks, preschool children sometimes mistakenly attribute memories to themselves rather than external sources, with decreasing source errors between 4‐ and 5‐years of age. In this research, we tested whether these developmental changes are also observed in spontaneously generated memories of personal life events. 4‐ and 5‐year olds generated life event memories and provided age estimates for when they took place. The children at both ages most often mentioned events that they could plausibly remember and some memories from external sources, including vicarious memories and events beyond their lifespan. Parents affirmed the accuracy of their children's memories and reported that some events were only told to or were imagined by the children. Our findings suggest that preschool children most often report events that they themselves remember and occasionally include events likely originating from external sources. These results add to the evidence showing that children's memories for events can be accurate. [ABSTRACT FROM AUTHOR]

The article provides information on the findings of a study on the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse model. A stable monoclonal antibodies (mAbs):Aβ complex is created by peripheral administration of anti-mAb in the plasma. The half-life of plasma Aβ is prolonged from minutes to days by binding mAbs to Aβ.

Bilingual children sometimes show delays relative to monolinguals on language tasks. In the present studies, we explored whether French–English bilinguals’ tense use and shift would show a developmental lag in the context of narration. In Study 1, we showed that both French and English monolinguals showed age-related changes in tense use, with preschoolers preferring the past and adults the present. A developmental lag among bilingual children could therefore take the form of prolonged use of the past tense through middle childhood. In Study 2, we observed tense use in the narratives of French–English bilingual children (8–10 years), as well as French and English monolinguals from the same age group. The bilinguals tended to use more present tense than the monolinguals. In qualitative analyses, bilinguals also used a multitude of expressive strategies, such as exclamations, repetitions and onomatopoeia, that made the stories more vivid. Taken together these results suggest that French–English bilinguals do not present developmental differences from monolinguals in tense use. Instead, they adopt an imagistic narrative style that differs from the monolinguals in multiple ways, including a greater use of the present tense. The adoption of this style might be linked to both bilingualism and a cultural preference among French–English bilinguals. [ABSTRACT FROM AUTHOR]

In this study we test how introversion–extroversion affects language and gesture use depending on whether the interlocutor is visible to the speaker. Adults described arrays of objects, half the time with a screen occluding their interlocutor and half the time with the interlocutor visible. When participants could not see their listener, they used more words, particularly concrete words and tended to gesture more . This difference was moderated by extroversion for gestures (i.e., extroverts gestured more when their interlocutor was occluded) but not for speech. We argue that visibility of a listener may influence how speakers use nonverbal feedback from their interlocutors differentially according to extroversion. In particular, visibility and personality may impact how speakers use gestures when they do not know whether their interlocutor has understood them. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Amyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 µM. Results: We find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency. Conclusion: These data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished. [ABSTRACT FROM AUTHOR]

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-β (Aβ) production. In cells, CRF treatment increases Aβ 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 β-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 Aβ. These data collectively link CRF to increased Aβ 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 Aβ and in some cases preferentially increase Aβ42 via complex effects on γ-secretase. [ABSTRACT FROM AUTHOR]

Accumulation of amyloid β protein (Aβ) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Aβ are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Aβ single-chain variable fragments (scFvs) as a potentially safer form of anti-Aβ immunotherapy. We have generated and characterized three anti-Aβ scFvs that recognize Aβ1-16, Aβx-40, or Aβx-42. To achieve widespread brain delivery, constructs expressing these anti-Aβ 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-Aβ scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Aβ deposition by 25-50%. These data suggest that intracranial anti-Aβ 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. [ABSTRACT FROM AUTHOR]

The article discusses the acute myocardial infarction to prevent adverse cardiac remodelling following acute myocardial infarction in the mouse. It aims to test the effects of modulation using a newly genetically engineered mouse antibody. It states that the study has been supported in part by funds from an American Heart Association Beginning Grant-in-aid.

Abstract: Ischemia/reperfusion (I/R) unleashes cellular events that threaten organ survival. I/R affects endoplasmic reticulum (ER) integrity and initiates the unfolded protein response (UPR). The adaptive arm of the UPR attenuates ER stress by increasing expression of chaperones promoting proper protein folding. However, failure to resolve ER stress leads to apoptotis. We recently showed that prolyl hydroxylase inhibition (PHI) attenuated post-ischemic cardiac injury. We hypothesized that PHI attenuated myocardial I/R injury through modulation of the UPR. We show for the first time that PHI activates all three regulatory arms of the UPR in murine microvascular endothelial cells and in mouse hearts. Cardiac I/R activated expression of pro-apoptotic CHOP (2.8 fold, n =3, p <0.01). PHI significantly decreased CHOP expression (50%, n =3, p <0.05) in post-ischemic hearts. PHI also induced activating transcription factor 4 (3.5 fold, n =3, p <0.001), glucose-regulated protein 78 (6 fold, n =3, p <0.001) and ER degradation-enhancing α-mannosidase-like protein (2.8 fold, n =3, p <0.001) expression in reperfusing hearts. Thus PHI resulted in significant reduction of apoptosis in post-ischemic myocardium. Our studies suggest that PHI induces protective ER stress proteins and attenuates post-ischemic myocardial damage by decreasing the pro-apoptotic components of the UPR. [Copyright &y& Elsevier]

Analyses of the biologic effects of mutations in the BRI2 (ITM2b) and the amyloid β 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-Aβ1- 40 transgenes in APP mouse models. Expression of BRI2-Aβ1- 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 Aβ 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 Aβ aggregation in vitro and mediates its anti-amyloidogenic effect in vivo. These studies demonstrate that BRI2 is a novel mediator of Aβ deposition in vivo. [ABSTRACT FROM AUTHOR]

γ-Secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of γ-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that γ-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of γ-secretase. Moreover, the level of EGFR is inversely correlated with the level of γ-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of γ-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking γ-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as compared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of γ-secretase and that mice with genetic reduction of γ-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer. [ABSTRACT FROM AUTHOR]

Numerous studies have established a pivotal role for Aβ42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Aβ40 is the predominant form of amyloid β(Aβ) 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 Aβ40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Aβ40 mice that selectively express high levels of Aβ40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Aβ42A mice expressing Aβ42 selectively and analyzed parenchymal and cerebrovascular Aβ deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Aβ40 decreased Aβ deposition by 60-90%. These results demonstrate that Aβ42 and Aβ40 have opposing effects on amyloid deposition: Aβ42 promotes amyloid deposition but Aβ40 inhibits it. In addition, increasing Aβ40 levels protected BRI-Aβ40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Aβ40 with respect to amyloid deposition suggest that strategies that preferentially target Aβ40 may actually worsen the disease course and that selective increases in Aβ40 levels may actually reduce the risk for development of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide eβential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is leβ clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD. Results: Adeno-aβociated viral (AAV) vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expreβion and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpreβion of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, paβive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tiβue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpreβion resulted in elevated levels of detergentinsoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expreβing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits. Conclusion: The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology in vivo, and demonstrate that whilst expreβion of Aβ42 alone is sufficient to initiate Aβ deposition, both Aβ40 and Aβ42 may contribute to cognitive deficits. [ABSTRACT FROM AUTHOR]