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Based on research with eight to eleven-year-old girls from the South of England, I discuss the relationship between their clothes, identity, temporality, life course and the ageing process. Despite media accounts suggesting the passivity of pre-teen girls’ fashionable dress consumption, unknowingly becoming prematurely sexualised through hyper-feminine dress, by using the interlinking of materiality and life course as a lens to explore girls’ understanding of fashion, my research showed that girls engage with popular debates about age-appropriate dress. I demonstrate that the participants were aware of sexual generationing and explored older, hyper-feminine, sexualised identities at specific, socially-approved times. Most significantly, this materiality/life course approach offers new insights into how girls explore the past, present and the future, feeling the passing of time and the ageing process on their bodies, through the materiality of their clothes. It is through dress that girls come to understand age, temporality and where they are on their life course.

International audience; INTRODUCTION: There is a growing interest in personality evaluation in Parkinson's disease (PD), following observations of specific temperaments in PD patients. Therefore, our objective was to evaluate personality dimensions from the Temperament and Character Inventory (TCI) in a cohort of fluctuating PD patients considered for deep brain stimulation. METHODS: Fluctuating PD patients from the PREDISTIM cohort were included. Description of TCI dimensions and comparison with a French normative cohort were performed. Pearson correlations between TCI dimensions and motor, behavioral and cognitive variables were investigated. Structural and internal consistency analysis of the TCI were further assessed. RESULTS: The 570 PD patients presented significant higher scores in Harm Avoidance, Reward Dependence, Persistence, Self-Directedness and Cooperativeness and significant lower scores in Self-Transcendence compared to the French normative cohort; only Novelty Seeking scores were not different. Harm Avoidance and Self-directedness scores were correlated with PDQ-39 total, HAMD, HAMA scores, and anxiolytic/antidepressant treatment. Novelty Seeking scores were correlated with impulsivity. Pearson correlations between TCI dimensions, principal component analysis of TCI sub-dimensions and Cronbach's alpha coefficients showed adequate psychometric proprieties. CONCLUSION: The TCI seems to be an adequate tool to evaluate personality dimensions in PD with good structural and internal consistencies. These fluctuating PD patients also have specific personality dimensions compared to normative French population. Moreover, Harm Avoidance and Self-Directedness scores are associated with anxio-depressive state or quality of life and, and Novelty Seeking scores with impulsivity.

Upper Normandy has several disadvantages in terms of access to dental health care for disabled people: an insufficient medical population, a lack of dental schools and dental care networks.A cross-sectional epidemiological investigation, using a questionnaire form, was carried out between November 2014 and February 2015 with a cohort of dentists in this region.The topics on this form focused firstly on accessibility and compliance with standards of dental offices and the influencing factors which are hampering their accessibility implementation, and secondly on the oral care of disabled patients by practitioners of this region : the impact of incentives, influencing factors which are complicating the dental care and the usage of private and public structures.If the care of disability concerns most practitioners, an apprehension is observed in the adaptation of these doctors' treatment protocols for these specific patients. The expectations of dentists concerning disability are multiple : the creation of specific care networks, better coordination of medical and social actors, and specific training programs concerning the dental care of disabled patients.

Trained in France, I have been practising in Belgium since 2015. As general practitioner, I also hold a diploma in palliative care, a degree requiring 2 years of training and placements. Before coming to Belgium, I practised in France in a mobile hospital and community palliative care team, and in a palliative care unit.Early significant dealings with practises in Belgium happened during my studies when a physician in a Belgian community palliative care team came to give a lecture in Lille, where he told us about his practise of euthanasia. We were confounded by this ‘medical capacity to take away a life’!

Upper Normandy has several disadvantages in terms of access to dental health care for disabled people: an insufficient medical population, a lack of dental schools and dental care networks.A cross-sectional epidemiological investigation, using a questionnaire form, was carried out between November 2014 and February 2015 with a cohort of dentists in this region.The topics on this form focused firstly on accessibility and compliance with standards of dental offices and the influencing factors which are hampering their accessibility implementation, and secondly on the oral care of disabled patients by practitioners of this region : the impact of incentives, influencing factors which are complicating the dental care and the usage of private and public structures.If the care of disability concerns most practitioners, an apprehension is observed in the adaptation of these doctors' treatment protocols for these specific patients. The expectations of dentists concerning disability are multiple : the creation of specific care networks, better coordination of medical and social actors, and specific training programs concerning the dental care of disabled patients.

Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I(1)(PP2A)) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I(1)(PP2A) can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I(1)(PP2A). In the adult AAV1-I(1)(PP2A) rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I(1)(PP2A) animals, suggesting that I(1)(PP2A) can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I(1)(PP2A) induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I(1)(PP2A) can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.

A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT) provides protection in a rat model for Alzheimer’s disease (AD). In this model, viral expression of the phosphoprotein phosphatase 2A (PP2A) endogenous inhibitor, the I2PP2A or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic β-amyloid protein. Dietary supplementation with EHT for 6–12 months resulted in substantial amelioration of all of these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiological studies indicating the coffee drinkers have substantially lowered risk of developing AD.

Besides the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles, neurogenesis and synaptic plasticity are markedly impaired in Alzheimer's disease (AD) possibly contributing to cognitive impairment. In this context, neurotrophic factors serve as a promising therapeutic approach via utilization of regenerative capacity of brain to shift the balance from neurodegeneration to neural regeneration. However, besides more conventional "bystander" effect, to what extent can neurotrophic compounds affect underlying AD pathology remains questionable. Here we investigated the effect of chronic oral treatment with a ciliary neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGL(A)G-NH2), on disease pathology both at moderate and severe stages in a transgenic mouse model of AD. 3xTg-AD and wild type female mice were treated for 12months with P021 or vehicle diet starting at 9-10months of age. A significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology associated sites was observed. The effect of P021 on Aβ pathology was limited to a significant decrease in soluble Aβ levels and a trend towards reduction in Aβ plaque load in CA1 region of hippocampus, consistent with reduction in Aβ generation and not clearance. This disease modifying effect was probably via increased brain derived neurotrophic factor (BDNF) expression mediated decrease in glycogen synthase kinase-3-β (GSK3β) activity we found in P021 treated 3xTg-AD mice. P021 treatment also rescued deficits in cognition, neurogenesis, and synaptic plasticity in 3xTg-AD mice. These findings demonstrate the potential of the neurotrophic peptide mimetic as a disease modifying therapy for AD.

Down syndrome (DS), caused by trisomy 21, is the most common genetic cause of intellectual disability and is associated with a greatly increased risk of early-onset Alzheimer’s disease (AD). The Ts65Dn mouse model of DS exhibits several key features of the disease including developmental delay and AD-like cognitive impairment. Accumulating evidence suggests that impairments in early brain development caused by trisomy 21 contribute significantly to memory deficits in adult life in DS. Prenatal genetic testing to diagnose DS in utero, provides the novel opportunity to initiate early pharmacological treatment to target this critical period of brain development. Here, we report that prenatal to early postnatal treatment with a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic, Peptide 021 (P021), rescued developmental delay in pups and AD-like hippocampus-dependent memory impairments in adult life in Ts65Dn mice. Furthermore, this treatment prevented pre-synaptic protein deficit, decreased glycogen synthase kinase-3beta (GSK3β) activity, and increased levels of synaptic plasticity markers including brain derived neurotrophic factor (BNDF) and phosphorylated CREB, both in young (3-week-old) and adult (~ 7-month-old) Ts65Dn mice. These findings provide novel evidence that providing neurotrophic support during early brain development can prevent developmental delay and AD-like memory impairments in a DS mouse model.

The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) is well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I2(PP2A). In AD brain, PP2A activity is compromised, probably because I2(PP2A) is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I2CTF, and both fragments inhibit PP2A. Here, we analyzed the spinal cords from ALS and control cases for I2(PP2A) cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I2(PP2A) into I2NTF and I2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I2(PP2A), we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I2CTF. AAV1-I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5-8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10-14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I2(PP2A) and the potential of I2(PP2A)-based therapeutics for these diseases.

Alzheimer's disease is multifactorial and involves several different mechanisms. The sporadic form of the disease accounts for over 99% of the cases. As of yet, there is no practical and widely available animal model of the sporadic form of the disease. In the Alzheimer's disease brain, the lysosomal enzyme asparaginyl endopeptidase is activated and translocated from the neuronal lysosomes to the cytoplasm, probably due to brain acidosis caused by ischemic changes associated with age-associated microinfarcts. The activated asparaginyl endopeptidase cleaves inhibitor-2 of protein phosphatase-2A, I2(PP2A), into I(2NTF) and I(2CTF) which translocate to the neuronal cytoplasm and inhibit the protein phosphatase activity and consequently the abnormal hyperphosphorylation of tau. Employing adeno-associated virus serotype 1 (AAV1) vector containing I(2NTF-CTF) and transduction of the brains of newborn rat pups with this virus, an animal model has been generated. The AAV1-I(2NTF-CTF) rats show neurodegeneration and cognitive impairment at 4 months and abnormal hyperphosphorylation and aggregation of tau and intraneuronal accumulation of amyloid-β at 13 months. The AAV1-I(2NTF-CTF) rats not only offer a disease-relevant model of the sporadic form of Alzheimer's disease but also represent a practical and widely available animal model. This short perspective on the need to focus on and develop the disease-relevant models of the sporadic form of Alzheimer's disease very much reflects the thinking of Inge Grundke-Iqbal who passed away on September 22, 2012 and to whom this article is dedicated.

Alzheimer's disease (AD) involves several possible molecular mechanisms, including impaired brain insulin sig- naling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month-old 3xTg-AD mice and stud- ied the cognitive function as well as AD-like brain abnormal- ities, such as tau phosphorylation and Aβ accumulation, 3- 6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We alsoobservedanincreaseintauhyperphosphorylationand neuroinflammation, a disturbance of brain insulin signaling, andadecreaseinsynapticplasticityandamyloid βpeptidesin the brain after STZ treatment. The expression of 20 AD- related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apo- ptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of meta- bolic insult in AD.

Alzheimer’s disease (AD) can be divided into sporadic AD (SAD) and familial AD (FAD). Most AD cases are sporadic and result from multiple etiologic factors, including environmental, genetic and metabolic factors, whereas FAD is caused by mutations in the presenilins or amyloid-β (Aβ) precursor protein (APP) genes. A commonly used animal model for AD is the 3xTg-AD transgenic mouse model, which harbors mutated presenilin 1, APP and tau genes and thus represents a model of FAD. There is an unmet need to in the field to characterize animal models representing different AD mechanisms, so that potential drugs for SAD can be evaluated preclinically in these animal models. A mouse model generated by intracerebroventricular (icv) administration of streptozocin (STZ), the icv-STZ mouse, shows many aspects of SAD. In this study, we compared the non-cognitive and cognitive behaviors as well as biochemical and immunohistochemical alterations between the icv-STZ mouse and the 3xTg-AD mouse. We found that both mouse models showed increased exploratory activity as well as impaired learning and spatial memory. Both models also demonstrated neuroinflammation, altered synaptic proteins and insulin/IGF-1 (insulin-like growth factor-1) signaling, and increased hyperphosphorylated tau in the brain. The most prominent brain abnormality in the icv-STZ mouse was neuroinflammation, and in the 3xTg-AD mouse it was elevation of hyperphosphorylated tau. These observations demonstrate the behavioral and neuropathological similarities and differences between the icv-STZ mouse and the 3xTg-AD mouse models and will help guide future studies using these two mouse models for the development of AD drugs.

Background The recent spread of positron emission tomography-computed tomography (PET/CT) poses extremity dosimetry challenges. The question arose whether the radiation dose measured by the ring thermoluminescent dosimeter usually worn on the proximal phalanx (P1) of the index finger measures doses that are representative of the true doses received by the upper extremities of the operators. A prospective individual dosimetry study was performed in which the personal equivalent dose Hp (0.07) received during a specific 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) manual dose-dispensing procedure was measured in a paired design by two operational personal electronic dosimeters fitted on the palm side of the index finger, namely in the P1 and distal phalanx (P3) positions. The study participants were ten nuclear medicine technologists working in two nuclear medicine departments. The personal equivalent radiation doses received by the palm side of the proximal phalanx of the index finger [Hp (0.07)P1] and that received by the distal phalanx [Hp (0.07)P3] were compared. Results The median Hp (0.07)P3/Hp (0.07)P1 ratio per participant varied between 1.0 and 2.5 (based on 23 to 31 measurements per participant). The 271 paired measurements revealed a crude Hp (0.07)P3/Hp (0.07)P1 ratio of 1.67, significantly different from 1 (p = 0.0004, 95 % CI [1.35–2.07]). When adjusted on participant’s gender and mother vial activity, the ratio was similar (1.53, p = 0.003, 95 % CI [1.22–1.92]). Conclusions The study demonstrated a significant disparity that may exist between the radiation doses measured in the P1 and P3 positions of operators during 18F-FDG manipulation. These findings emphasize the importance of performing workplace dosimetry studies adapted to each radiopharmaceutical and manipulation thereof, aiming to guarantee optimal workers’ dosimetry monitoring schemes. Trial registration Hospital Nursing and Paramedical Research Program (PHRIP, 2011–2013) from the French Ministry of Health (DGOS), http://social-sante.gouv.fr/IMG/pdf/Resultats_PHRIP_2011.pdf

Deficiency of protein phosphatase-2A is a key event in Alzheimer’s disease. An endogenous inhibitor of protein phosphatase-2A, inhibitor-1, I1 PP2A, which inhibits the phosphatase activity by interacting with its catalytic subunit protein phosphatase-2Ac, is known to be upregulated in Alzheimer’s disease brain. In the present study, we overexpressed I1 PP2A by intracerebroventricular injection with adeno-associated virus vector-1-I1 PP2A in Wistar rats. The I1 PP2A rats showed a decrease in brain protein phosphatase-2A activity, abnormal hyperphosphorylation of tau, neurodegeneration, an increase in the level of activated glycogen synthase kinase-3beta, enhanced expression of intraneuronal amyloid-beta and spatial reference memory deficit; littermates treated identically but with vector only, i.e., adeno-associated virus vector-1-enhanced GFP, served as a control. Treatment with memantine, a noncompetitive NMDA receptor antagonist which is an approved drug for treatment of Alzheimer’s disease, rescued protein phosphatase-2A activity by decreasing its demethylation at Leu309 selectively and attenuated Alzheimer’s disease-like pathology and cognitive impairment in adeno-associated virus vector-1-I1 PP2A rats. These findings provide new clues into the possible mechanism of the beneficial therapeutic effect of memantine in Alzheimer’s disease patients.

Adult neurogenesis, the production of new neurons in certain brain regions, is known to decrease with age and the loss of neurogenic potential has been implicated in Alzheimer's disease (AD), a leading cause of dementia in the elderly. Cerebrolysin (CBL) has been shown to increase neurogenesis in models of stroke and AD. CBL is composed of small peptides with activity similar to neurotrophic factors including ciliary neurotrophic factor (CNTF), which may mediate its neurogenic effects. This study compares the effects of CBL and two peptides with corresponding to an active region of CNTF (Peptide 6 and 6A) across neurogenic brain regions in amyloid-β protein precursor (AβPP) transgenic (tg) mice. Both CBL and Peptides 6 and 6A were able to increase the numbers of neuroblasts (DCX+ cells) and BrdU+ cells in a regionally specific manner across the subventricular zone, olfactory bulb, and hippocampus. The increased generation of new cells and cell survival in animals treated with Peptides 6 and 6A was accompanied by an increase in PCNA+ cells. In contrast, AβPP tg mice treated with CBL displayed reduced levels of TUNEL staining, while levels of PCNA were unaltered. Collectively these results demonstrate that while CBL and Peptides 6 and 6A all potentiate neurogenesis in the AβPP tg mice, their relative modes of action may differ with CBL associated with reduced apoptosis and Peptides 6 and 6A working by augmenting cell proliferation. These results are consistent with a potential therapeutic relevance for Peptides 6 and 6A in AD and other disorders characterized by neurogenic deficits.

Down syndrome (DS) is caused by the triplication of ∼240 protein-coding genes on chromosome 21 and is the most prevalent form of developmental disability. This condition results in abnormalities in many organ systems, as well as in intellectual retardation. Many previous efforts to understand brain dysfunction in DS have indicated that cognitive deficits are coincident with reduced synaptic plasticity and decreased neuronal proliferation. One therapeutic strategy for optimizing the microenvironment for neuronal proliferation and synaptic plasticity in the brain is the use of neurotrophins to restore the homeostasis of the brain biochemical milieu. Here, we show that peripheral administration of Peptide 6, an 11-mer corresponding to an active region of ciliary neurotrophic factor, amino acid residues 146 to 156, can inhibit learning and memory impairments in Ts65Dn mice, a trisomic mouse model of DS. Long-term treatment with Peptide 6 enhanced the pool of neural progenitor cells in the hippocampus and increased levels of synaptic proteins crucial for synaptic plasticity. These findings suggest a therapeutic potential of Peptide 6 in promoting functional neural integration into networks, thereby strengthening biologic substrates of memory processing.

In addition to the occurrence of numerous neurofibrillary tangles and Aβ plaques, neurogenesis and neuronal plasticity are markedly altered in Alzheimer disease (AD). Although the most popular therapeutic approach has been to inhibit neurodegeneration, another is to promote neurogenesis and neuronal plasticity by utilizing the regenerative capacity of the brain. Here we show that, in a transgenic mouse model of AD, 3xTg-AD mice, there was a marked deficit in neurogenesis and neuroplasticity, which occurred before the formation of any neurofibrillary tangles or Aβ plaques and was associated with cognitive impairment. Furthermore, peripheral administration of Peptide 6, an 11-mer, which makes an active region of ciliary neurotrophic factor (CNTF, amino acid residues 146-156), restored cognition by enhancing neurogenesis and neuronal plasticity in these mice. Although this treatment had no detectable effect on Aβ and tau pathologies in 9-month animals, it enhanced neurogenesis in dentate gyrus, reduced ectopic birth in the granular cell layer, and increased neuronal plasticity in the hippocampus and cerebral cortex. These findings, for the first time, demonstrate the possibility of therapeutic treatment of AD and related disorders by peripheral administration of a peptide corresponding to a biologically active region of CNTF.

Development of rational therapeutic treatments of Alzheimer disease (AD) requires the elucidation of the etiopathogenic mechanisms of neurofibrillary degeneration and β-amyloidosis, the two hallmarks of this disease. Here we show, employing an adeno-associated virus serotype 1 (AAV1)-induced expression of the C-terminal fragment (I2CTF) of I2PP2A, also called SET, in rat brain, decrease in protein phosphatase 2A (PP2A) activity, abnormal hyperphosphorylation of tau, and neurodegeneration; littermates treated identically but with vector only, i.e., AAV1-enhanced green fluorescent protein (GFP), served as a control. Furthermore, there was an increase in the level of activated glycogen synthase kinase-3β and enhanced expression of intraneuronal Aβ in AAV1-I2CTF animals. Morris water maze behavioral test revealed that infection with AAV1-I2CTF induced spatial reference memory and memory consolidation deficits and a decrease in the brain level of pSer133-CREB. These findings suggest a novel etiopathogenic mechanism of AD, which is initiated by the cleavage of I2PP2A, producing I2CTF, and describe a novel disease-relevant nontransgenic animal model of AD.—Wang, X., Blanchard, J., Kohlbrenner, E., Clement, N., Linden, R. M., Radu, A., Grundke-Iqbal, I., Iqbal, K. The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment.

Development of neurotrophic peptidergic drugs that can mimic neurotrophins and promote neurogenesis and maturation of newborn cells into mature functional neurons represents an exciting therapeutic opportunity for treatment of Alzheimer disease and other learning and memory disorders as well as enhancing cognition of normal individuals. Here we report the design of a peptidergic compound, Ac-DGGLAG-NH2, called P21, when administered peripherally, enhanced learning as well as both short-term and spatial reference memories of normal adult C57Bl6 mice. P21 induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

APP(751SL) mice of 5-6- and 7-8-month-old and their wild-type littermates were submitted to one-session learning in a water-maze with three levels of training (4, 12 or 22 trials). Training consisted in finding a submerged platform with a fixed location and marked by a cue. During testing two platforms were presented: one consistent with the spatial location allowing place-response (PR) and the other signaled by the cue enabling cued-response (CR). When testing occurred 24h after training, wild-type and 5-6-month-old APP(751SL) mice exhibited a shift in response strategy as a function of training level, by executing CR when trained with 4 trials and PR when trained with 12 trials, but 7-8-month-old APP(751SL) mice executed only CR. However, they displayed PR when tested 1h after 12- and 22-trial, suggesting a consolidation deficit. Zif268 imaging showed plasticity impairment of the hippocampal-dependent memory system but not of the dorsolateral caudate nucleus. Moreover, in these APP(751SL) mice, the deficit selectively affecting hippocampal function cannot be directly related to the onset of beta-amyloid deposits.

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

Sporadic Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by progressive neurodegeneration. Decreased brain energy and glucose metabolism occurs before the appearance of AD symptoms and worsens while the disease progresses. Deregulated brain insulin signaling has also been found in AD recently. To restore brain insulin sensitivity and glucose metabolism, pioglitazone and rosiglitazone, two insulin sensitizers commonly used for treating type 2 diabetes, have been studied and shown to have some beneficial effects in AD mouse models. However, the molecular mechanisms of the beneficial effects remain elusive. In the present study, we treated the 3xTg-AD mice, a widely used mouse model of AD, with pioglitazone and rosiglitazone for 4 months and studied the effects of the treatments on cognitive performance and AD-related brain alterations. We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanisms by which these two insulin sensitizers might be useful for treating AD and support further clinical trials evaluating the efficacy of these drugs.

suggested to impair hippocampal neurogenesis, which can be linked to cognitive decline in aging and AD. The a 7 nAChRs play an important role in modulating synaptic plasticity in the hippocampus and we have previously reported an increased expression of a 7 nAChRs on reactive astrocytes in AD postmortem brain (Yu et al., 2005). Here we propose that stimulating a 7 nAChR signaling induces a favorable brain microenvironment, which could enhance repair processes and ameliorate cognitive impairment. Methods: Different aspects of neuroinflammation in relation to AD pathogenesis were investigated. i) First, human microglia cells were exposed to beta-amyloid 42 at nM concentrations and we studied how the secretion of pro-inflammatory cytokines released in cell media affected human stem cell neuronal differentiation in vitro. ii) Later, to evaluate astroglial processes in relation to neurogenesis in vivo, we used AD Tg2576 mice, which were treated with daily i.p. injections for 5 weeks with the partial a 7 nAChR agonist JN403 (0.03 mg/kg) in combination with bilateral human neural stem cell (hNSC) transplantation in the hippocampus. Results: Surprisingly, microglia exposed to fibrillary beta-amyloid 42, decreased secretion of cytokines TNF a, IL-1 band IL-2, which in turn impaired human stem cells differentiation(p

Alzheimer's disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, I2PP2A, from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of I2PP2A , also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF-CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF-CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF-CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF-CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.

synergistically increased brain phosphatides, synaptic proteins, and dendritic spines formation (Wurtman, 2009). The Fortasyn Connect multi-nutrient concept improved membrane integrity, thereby influencing membrane-dependent processes such as receptor function and amyloid precursor protein processing, as shown by reduced Abeta production and plaque burden, as well as Abeta toxicity (Kamphuis, 2009). This multi-nutrient supplementation may also have neuroprotective effects by reducing lipid-peroxidation and vascular damage. Conclusions: Together, these insights provided the basis for the development of Souvenaid , a multi-nutrient drink for patients with AD containing Fortasyn Connect, and designed to enhance synapse formation in AD. The effect of Souvenaid on memory and cognitive performance was recently assessed in a proof-of-concept study, Souvenir I, with 212 drug-naive mild AD patients (MMSE 20-26). The study showed that oral nutritional supplementation with Souvenaid given for 12 weeks improves memory in patients with mild AD (Scheltens, 2010). To confirm and extend these findings, three additional studies were initiated. Two studies will be completed in 2011 and one study will be completed in 2013.

Alzheimer's disease occurs both in familial and or sporadic forms. The familial AD accounts for less than 1% of the cases and is caused by specific mutations in amyloid precursor protein, presenilin 1 or presenilin 2 genes. The nature of the etiological factors for the sporadic form of AD, which accounts for over 99% of the cases, is at present not well understood. To date most of the animal models are transgenic mice which express the familial AD mutations alone or in combination with tau mutations of frontotemporal dementia. This chapter discusses the sparseness of animal models of sporadic AD and describes a novel adeno associated virus (AAV) vector-induced experimental rat model of this disease. This model replicates the overexpression of the C-terminal fragment of I2PP2A, I2CTF, in rat brain using the AAV vector. The AAV-I2CTF rats show intraneuronal accumulation of Ab1–42 and abnormally hyperphosphorylated tau but no Ab plaques or neurofibrillary tangles by nine months, studied so far, but are cognitively impaired in Morris water maze spatial reference memory task. As compared with generation of transgenic animals, the AAV-induced expression system is rapid, highly reproducible, and within the reach of most research laboratories as well as allows the expression of the desired gene in a spatial and temporal controlled manner.

Alzheimer's disease occurs both in familial and or sporadic forms. The familial AD accounts for less than 1% of the cases and is caused by specific mutations in amyloid precursor protein, presenilin 1 or presenilin 2 genes. The nature of the etiological factors for the sporadic form of AD, which accounts for over 99% of the cases, is at present not well understood. To date most of the animal models are transgenic mice which express the familial AD mutations alone or in combination with tau mutations of frontotemporal dementia. This chapter discusses the sparseness of animal models of sporadic AD and describes a novel adeno associated virus (AAV) vector-induced experimental rat model of this disease. This model replicates the overexpression of the C-terminal fragment of I2PP2A, I2CTF, in rat brain using the AAV vector. The AAV-I2CTF rats show intraneuronal accumulation of Ab1–42 and abnormally hyperphosphorylated tau but no Ab plaques or neurofibrillary tangles by nine months, studied so far, but are cognitively impaired in Morris water maze spatial reference memory task. As compared with generation of transgenic animals, the AAV-induced expression system is rapid, highly reproducible, and within the reach of most research laboratories as well as allows the expression of the desired gene in a spatial and temporal controlled manner.

A therapeutic strategy against cognitive disorders like A lzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic fact ors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic fa ctor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skele tal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuron al commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal- dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition.

Independent of the aetiology, AD (Alzheimer's disease) neurofibrillary degeneration of abnormally hyperphosphorylated tau, a hallmark of AD and related tauopathies, is apparently required for the clinical expression of the disease and hence is a major therapeutic target for drug development. However, AD is multifactorial and heterogeneous and probably involves several different aetiopathogenic mechanisms. On the basis of CSF (cerebrospinal fluid) levels of Abeta(1-42) (where Abeta is amyloid beta-peptide), tau and ubiquitin, five different subgroups, each with its own clinical profile, have been identified. A successful development of rational therapeutic disease-modifying drugs for AD will require understanding of the different aetiopathogenic mechanisms involved and stratification of AD patients by different disease subgroups in clinical trials. We have identified a novel aetiopathogenic mechanism of AD which is initiated by the cleavage of SET, also known as inhibitor-2 (I(2)(PP2A)) of PP2A (protein phosphatase 2A) at Asn(175) into N-terminal (I(2NTF)) and C-terminal (I(2CTF)) halves and their translocation from the neuronal nucleus to the cytoplasm. AAV1 (adeno-associated virus 1)-induced expression of I(2CTF) in rat brain induces inhibition of PP2A activity, abnormal hyperphosphorylation of tau, neurodegeneration and cognitive impairment in rats. Restoration of PP2A activity by inhibition of the cleavage of I(2)(PP2A)/SET offers a promising therapeutic opportunity in AD with this aetiopathogenic mechanism.

Despite huge advances on Alzheimer's disease (AD) etiology, the clinical diagnosis remains the unique commonly used tool to detect the onset of the disease. For instance, epidemiological studies report that the combination of episodic and working memory disorders represents the most consistent sign of progression from mild cognitive impairment to AD. However, such working memory disorders failed to be observed early in transgenic mouse models of AD because the behavioral procedures used do not tackle properly crucial components of working memory. The aim of the present work was to assess early occurrence of working memory impairments in APP 751SL mice. Therefore, we designed a new behavioral task in the water-maze, based on the principle of a delayed matching to place task, where spatial recognition was assessed for four different platform locations within a single session. First, we showed that dorsal hippocampal but not medial prefrontal cortex lesions in C57Bl6 mice induced a time-dependent impairment of spatial recognition. Then, the hippocampal-like memory alterations were reproduced in 7–8-month-old APP 751SL mice but not in younger animals (5–6-month-old). We also demonstrated that these working memory deficits are related to progressive Aβ accumulation in the hippocampus, but not in the other selected brain structures.

Pharmacological enhancement of hippocampal neurogenesis is a therapeutic approach for improvement of cognition in learning and memory disorders such as Alzheimer's disease. Here we report the development of an 11-mer peptide that we designed based on a biologically active region of the ciliary neurotrophic factor. This peptide, Peptide 6, induced proliferation and increased survival and maturation of neural progenitor cells into neurons in the dentate gyrus of normal adult C57BL6 mice. Furthermore, Peptide 6 increased the MAP2 and synaptophysin immunoreactivity in the dentate gyrus. Thirty-day treatment of the mice with a slow release bolus of the peptide implanted subcutaneously improved reference memory of the mice in Morris water maze. Peptide 6 has a plasma half life of over 6 h, is blood-brain barrier permeable, and acts by competitively inhibiting the leukemia inhibitory factor signaling. The fact that Peptide 6 is both neurogenic and neurotrophic and that this peptide is effective when given peripherally, demonstrates its potential for prevention and treatment of learning and memory disorders.

Current transgenic mouse models of Alzheimer disease constitute a relevant tool to examine the relationships between neuropathological lesions, neurodegeneration and clinical syndromes. Nevertheless, addressing the relation between Aβ deposition and cognition deterioration requires careful adjustment for age to decipher underlying mechanisms of impairments and identify potential therapeutic targets. In the present work we have carried out a detailed behavioral analysis of the APP 751SL transgenic mouse model testing 6 age-points (from 2 to 19–20 months) and estimating in parallel the cerebral Aβ deposition. The immunohistochemistry study indicated a fast progression of Aβ 17–24 staining in several brain structures that reached for most of them, a maximal level at 7–8 months of age. Behavioral experiments showed that APP751SL mice displayed alterations in some general functions (muscular strength, motor activity) whereas other functions are preserved (anxiety, exploration). Acquisition and extinction of an appetitive operant conditioning were used to assess early learning deficits. Hippocampal but not dorso-lateral striatal lesion was shown to delay extinction. Although some learning deficits were detected at 5–6 months in the acquisition of the operant conditioning task, more robust impairments in extinction were observed in 7–8-month-old mice. Indeed, spatial memory deficit was associated to a selective hippocampal CA1 impairment of learning-induced Zif268 activation. Because this mouse model displayed gradual memory deficits it gives the opportunity to investigate the temporal progression of molecular and cellular mechanisms that induce cognitive decline.