Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer’s disease

International audienceAlzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown , a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid b (Ab) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Ab-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal Ab levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and g oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were Ab-independent. Our results could partly explain the limited efficacy of Ab-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD

Age-related vulnerability of pattern separation in C57BL/6J mice

International audienceAging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age-dependence which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets

Modulation de l'expression de différents ARNM et/ou protéines au cours de la différenciation induite par le VIP, le PACAP et le PHM dans des cellules de neuroblastome humain

Le vasoactive intestinal peptide (VIP), le pituitary adenylate cyclase-activating polypeptide (PACAP) et le peptide histidine methionine (PHM) sont des neuropeptides apparentés connus pour réguler la prolifération et/ou la différenciation de cellules normales et tumorales. Dans le travail décrit ici, la neuritogénèse induite par ces neuropeptides dans les cellules SH-SY5Y de neuroblastome humain cultivées en milieu sans sérum a été caractérisée aux niveaux morphologique et moléculaire. Cette neuritogénèse était associée à une modulation de l'expression des ARNm et/ou des protéines marqueurs de la différenciation neuronale tels que des protéines du cytosquelette (neurofilaments, ß-tubuline III, MAP2, doublecortine), la protéine synaptique SNAP-25 et le facteur de transcription Brn-3a. Les résultats indiquent que le VIP a induit un état de différenciation plus avancé que le PACAP, lui-même induisant un état moins immature que le PHM, et suggèrent que Brn-3a pourrait être impliqué dans la différenciation induite par le VIP et le PACAP dans les cellules SH-SY5Y.Vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and peptide histidine methionine (PHM) are related neuropeptides known to regulate proliferation and/or differentiation in normal and tumoral cells. In the work described here, neuritogenesis induced by these neuropeptides in human neuroblastoma SH-SY5Y cells cultured in serum-free medium was charaterized at the morphological and molecular levels. This neuritogenesis was associated with a modulation of the mRNA and/or protein expression of neuronal differentiation markers such as cytoskeleton proteins (neurofilaments, ß-tubulin III, MAP2, doublecortin), the synaptic protein SNAP-25 and the transcription factor Brn-3a. The results indicate that VIP induces a more advanced state of differentiation than PACAP, itself inducing a less immature state than PHM, and suggest that Brn-3a might be involved in the differentiation induced by VIP and PACAP in SH-SY5Y cells.POITIERS-BU Sciences (861942102) / SudocSudocFranceF

Feline cerebellare cortex neurons / neuroblasts permissivity to feline panleukopenia virus during the perinatal period

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Plaques amyloïdes et pathologie tau : modélisation de leur interaction dans des modèles murins développant les lésions de la maladie d’Alzheimer

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ABNORMAL PROCESSING AND MISFOLDING OF TAU IS MODULATED BY ENDOGENOUS TAU AND MUTANT APP/PS1 BUT NOT BY ENDOGENOUS APP IN TAU TRANSGENIC MICE

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Tau and GSK3beta

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Precocious Alterations of Brain Oscillatory Activity in Alzheimer’s Disease: A Window of Opportunity for Early Diagnosis and Treatment

International audienceAlzheimer's disease (AD) is the most common form of neurodegenerative dementia accounting for 50-80% of all age-related dementia. This pathology is characterized by the progressive and irreversible alteration of cognitive functions, such as memory, leading inexorably to the loss of autonomy for patients with AD. The pathology is linked with aging and occurs most commonly around 65 years old. Its prevalence (5% over 65 years of age and 20% after 80 years) constitutes an economic and social burden for AD patients and their family. At the present, there is still no cure for AD, actual treatments being moderately effective only in early stages of the pathology. A lot of efforts have been deployed with the aim of defining new AD biomarkers. Successful early detection of mild cognitive impairment (MCI) linked to AD requires the identification of biomarkers capable of distinguishing individuals with early stages of AD from other pathologies impacting cognition such as depression. In this article, we will review recent evidence suggesting that electroencephalographic (EEG) recordings, coupled with behavioral assessments, could be a useful approach and easily implementable for a precocious detection of AD

Expression of transferrin receptor 1, proliferating cell nuclear antigen, p27(Kip1) and calbindin in the fetal and neonatal feline cerebellar cortex.

Cerebellar cortices from feline fetuses with estimated gestational ages of 40-66days and from kittens aged 2days to 2months, all negative for feline panleukopenia virus (FPV) infection, were analysed for expression of the transferrin receptor 1 (TrFR1), proliferating cell nuclear antigen (PCNA), p27(Kip1) and calbindin. TrFR1, the receptor used by FPV to enter target cells, was expressed in capillary endothelial cells in the cerebellum at all fetal stages investigated and in Purkinje cells of a 3-week-old kitten, but not in the neuroblasts in the external granule layer (EGL). PCNA was expressed in cells of the superficial layer of the EGL. The cyclin-dependent kinase inhibitor p27(Kip1) was expressed in cells of the deep layer of the EGL. Purkinje cells expressed calbindin from the earliest fetal stage investigated. Co-expression of PCNA and calbindin could not be demonstrated, indicating that feline Purkinje cells are post-mitotic from at least 40days gestation.Journal ArticleSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Rapamycin Ester Analog CCI-779/Temsirolimus Alleviates Tau Pathology and Improves Motor Deficit in Mutant Tau Transgenic Mice.

Neurofibrillary tangles are intracellular inclusions made of tau protein that accumulates in neurons in Alzheimer's disease (AD) and in other tauopathies. We have investigated the ability of the rapamycin ester CCI-779/Temsilorimus, a mTOR inhibitor with better stability and pharmacological properties compared to rapamycin, to interfere with the development of a motor phenotype and tau pathology in a mutant tau mouse model developing neurofibrillary tangles, by stimulation of mTOR dependent macroautophagy. Mutant tau mice (Tg30) were treated with CCI-779 before onset of motor signs for 7 months (from 5 to 12 months of age) or after the onset of motor signs for 2 months (from 10 to 12 months of age). End-point motor deficits were 50% lower in the group of Tg30 mice treated for 7 months. Inhibition of mTOR signaling and stimulation of macroautophagy in the brain of CCI-779 treated Tg30 mice was suggested by decreased phosphorylation of mTOR downstream signaling molecules p70S6 kinase and Akt and increased level of the autophagy markers Rab7 and LC3-II. CCI-779 treatment decreased the brain levels of Sarkosyl-insoluble tau and phosphotau inTg30 mice both after 2 months or 7 months of treatment. The density of neurofibrillary tangles was significantly decreased when treatment was started prior onset of motor signs. These results indicate that stimulation of mTOR dependent autophagy by CCI-779 compound is efficient to counteract the accumulation of abnormal tau when administered early or late in a tauopathy model and to improve a motor deficit when started before onset of motor signs.SCOPUS: ar.jinfo:eu-repo/semantics/publishe