Targeting glutamatergic and cellular prion protein mechanisms of amyloid β-mediated persistent synaptic plasticity disruption: longitudinal studies

Alzheimer's disease amyloid-β (Aβ) oligomers are synaptotoxic, inappropriately increasing extracellular glutamate concentration and glutamate receptor activation to thereby rapidly disrupt synaptic plasticity. Thus, acutely promoting brain glutamate homeostasis with a blood-based scavenging system, glutamate-oxaloacetate transaminase (GOT), and blocking metabotropic glutamate 5 (mGlu5) receptor or its co-receptor cellular prion protein (PrP), prevent the acute inhibition of long-term potentiation (LTP) by exogenous Aβ. Here, we evaluated the time course of the effects of such interventions in the persistent disruptive effects of Aβ oligomers, either exogenously injected in wild type rats or endogenously generated in transgenic rats that model Alzheimer's disease amyloidosis. We report that repeated, but not acute, systemic administration of recombinant GOT type 1, with or without the glutamate co-substrate oxaloacetate, reversed the persistent deleterious effect of exogenous Aβ on synaptic plasticity. Moreover, similar repetitive treatment reversibly abrogated the inhibition of LTP monitored longitudinally in freely behaving transgenic rats. Remarkably, brief repeated treatment with an mGlu5 receptor antagonist, basimglurant, or an antibody that prevents Aβ oligomer binding to PrP, ICSM35, also had similar reversible ameliorative effects in the transgenic rat model. Overall, the present findings support the ongoing development of therapeutics for early Alzheimer's disease based on these complementary approaches

Distinct Transcriptome Expression of the Temporal Cortex of the Primate Microcebus murinus during Brain Aging versus Alzheimer's Disease-Like Pathology

Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, “AD-like” animals that presented ß-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and “AD-like” animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and “AD-like” in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in “AD-like” animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the “AD-like” group. Functional categorization showed that most of the genes that were up-regulated in healthy old animals and down-regulated in “AD-like” animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in “AD-like” animals. These results open the way to new exploration of physiological and “AD-like” aging in primates

Neuromodulation of the feedforward dentate gyrus-CA3 microcircuit

The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval

Glutamate receptors in preclinical research on Alzheimer\u27s disease: update on recent advances

The cognitive and related symptoms of Alzheimer\u27s disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimer\u27s disease amyloid ?-protein (A?) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. L-glutamate, the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble A? oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. A? exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, A?-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of A? have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating A? production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of A? and cellular mechanisms of synaptic failure in early AD

Nutrition Services for Children with Special Needs in Child Care Programs

Children with special needs are increasingly being served in community-based settings. Guidelines for out-of-home child care programs published by the American Public Health Association and the American Academy of Pediatrics recommend that child care facilities integrate children with disabilities and children without disabilities. The objectives of this study were to determine the nutrition services provided to children with special needs in child care programs and the continuing education needs of child care personnel related to providing these services. Pretested questionnaires were mailed to a random sample of 500 licensed day care homes and child care centers in a southeastern state. Two hundred forty-four programs (49%) serving 21,027 children completed questionnaires. Descriptive statistics were used to summarize data. Thirty-eight percent of programs reported serving children with special needs. A total of 403 children with special needs (an average of 4.3 children/program) were served. Programs reported serving children with special needs with food allergies/intolerances (55% of children served), growth problems (21%), feeding problems (8%), seizure disorders (7%), metabolic problems (3%), and a variety of other conditions including cystic fibrosis, Down syndrome, asthma, and extreme medical fragility requiring tube feeding. Thirty-three percent of programs responding reported making special nutritional provisions for children with special needs. Of 289 children for whom special provisions were made, menu changes were provided for 57%, recipe changes for 12%, texture changes for 9%, assistance with feeding for 9%, food provided by parents was served for 6%, special eating devices provided for 4%, and eating area modified for wheelchair access for 4%. Forty-eight percent of programs responding reported that they measured height and weight of children, and 96% reported that they monitored children\u27s eating. Continuing education needs identified included planning menus with more variety (48% reported moderate or high continuing education need), planning food and nutrition activities for the curriculum (44%), modifying recipes to decrease fat, sugar, and salt (44%), and planning menus that appeal to children (43%). The American Dietetic Association recommends that child care programs obtain consultation and guidance from a registered dietitian (RD) on a regular basis. Forty-five percent of child care programs in this study reported receiving consultation from a dietitian or nutritionist. The variety of nutritional needs of children with disabilities and chronic illnesses served by child care programs included in this study support the need for regular consultation and guidance by the RD. © 1995 American Dietetic Association