People with a diagnosis of schizophrenia have been found to perform poorly on tasks assessing semantic memory, and these impairments have been proposed to be related to certain symptoms, in particular Formal Thought Disorder (FTD). A systematic literature review and meta-analysis identified the need a) to determine whether semantic memory is a primary impairment in schizophrenia and not secondary to other cognitive impairments and b) what cognitive models could provide the best explanation for the impairment. With these aims, Studies One and Two compared the performance of a group of people with schizophrenia across a battery of semantic memory tests (Hodges, Salmon and Butters, 1992). In order to eliminate confounding variables, two clinical control groups were recruited for comparison, one with a probable degraded semantic memory arising from Alzheimer‘s Dementia (AD) and the other with a primary dysexecutive syndrome caused by acquired brain injury (ABI). From these comparisons, it was possible to profile the semantic memory impairment in schizophrenia with the conclusion that any deficits are task-specific. Unlike the AD group, the impairment did not seem to arise from a loss of stored knowledge but nor did a retrieval problem, in its simplest terms, offer the best explanation. Since the ABI group performed normally on the battery it is clear that a dysexecutive syndrome does not necessarily explain poor semantic memory performance. Qualitatively, the associations and categories formed by people with schizophrenia on tasks of semantic categorisation e.g. the Category Generation Test (CGT) (Green, Done, Anthony, McKenna and Ochocki, 2004) often resemble loosening of associations and psychotic speech. In order to understand more about the processes involved in the formation of these bizarre categories, I compared performance on the CGT of groups of people with schizophrenia, AD and ABI. I found that the people with AD performed fairly similarly to the people with schizophrenia in that they sorted cards in an idiosyncratic way but the ABI group performed normally, adhering to taxonomic categories. Although this result might suggest that the bizarre associations on the CGT in people with schizophrenia are caused by a deficit in semantic memory (and not a dysexecutive syndrome), further analysis found important differences between the AD and the schizophrenia group in the way the card sorts were formed. In addition, both these groups showed intact semantic memory knowledge of the items they mis-sorted, indicating that categorisation problems do not necessarily arise from a degraded memory store. The difficulties people with schizophrenia appear to have on tests of associations and categorisation (e.g. CGT) could arise from a disorganised semantic memory i.e. differences in the way in which concepts are interconnected. On the CGT, patients with schizophrenia were far more likely to sort items on the basis of thematic (situational) information suggesting a preference for thematic over taxonomic associations. To test this, participants were tested using a triadic comparison task which requires choosing whether an item is best associated with a taxonomic, thematic or perceptually related item. On this test patients performed comparably to controls suggesting that their semantic memory is organised normally and that the abnormalities in the way in which items are associated on some semantic memory tests, including the CGT, are task-specific. It has been proposed that one of the core problems in schizophrenia is that there is ―an aberrant assignment of salience‖ (Kapur 2003) to contextually inappropriate concepts due to a dysregulated dopamine system (Kapur 2003; Kapur et al 2005). It is possible that this could also explain the semantic memory impairments in schizophrenia i.e. certain less relevant concepts/ associations are chosen because they are experienced as more salient. To test this, a group of patients with schizophrenia were assessed using a test of semantic salience. Compared to controls, the patients made significantly more errors of salience including significantly more errors where large aberrant attributions of importance were given to items. The tendency to make errors on the salience test was highly correlated with errors on the CGT and also the semantic association tests, indicating a common underlying mechanism. Therefore, it can be concluded that the semantic memory impairments in schizophrenia are task-specific, not caused by a loss of semantic knowledge or a dysexecutive syndrome, but due to an aberrant assignment of salience to less relevant semantic concepts. More work is needed to understand the cognitive processes underlying this aberrant attribution process, and also the biological substrates involved.

The multi-cultural demographics of those who are diagnosed with Alzheimer’s disease should be closely examined. From a designer’s standpoint, its cultural traits can foster positive behaviors that lead to better quality of life for patients and caregivers. A patient-centered approach in design was explored in order to shape community-based care that empowers (1) individuality in care services, (2) interpersonal connection in caregiver–patient activities, and (3) a communal culture of being valued via humanitarian approaches.

This critical synopsis of prior work by Clive Beggs is submitted in support of a PhD by published work. The work focuses on venous and cerebrospinal fluid (CSF) anomalies associated with multiple sclerosis (MS) and other neurological diseases. MS is characterized by focal inflammatory lesions, which are often venocentric. Recently a vascular syndrome, chronic cerebrospinal venous insufficiency (CCSVI) has been linked with MS. This syndrome, which is characterized by constricted cerebral venous outflow, has become mired in controversy, with various studies producing conflicting findings, with the result that the science associated with CCSVI has become obscured. Clive Beggs work seeks to bring clarity to the debate surrounding CCSVI by characterizing physiological changes associated with constricted cerebral venous outflow. The work submitted here involves collaborative studies with Robert Zivadinov (University of Buffalo), Paolo Zamboni (University of Ferrara), and Chih- Ping Chung (National Yang Ming University of Medicine). The key findings of these studies are: (i) MS patients, diagnosed with CCSVI, exhibit greatly increased hydraulic resistance of the cerebral venous drainage system; (ii) MS patients experience loss of the small cerebral veins; (iii) MS patients exhibit reduced CSF bulk flow, consistent with mild venous hypertension; (iv) MS patients exhibit increased CSF pulsatility in the Aqueduct of Sylvius, which appears to be linked with mild venous hypertension associated with CCSVI; and (v) jugular venous reflux is associated with white matter and parenchymal volumetric changes in Alzheimer’s patients. Collectively, these findings suggest that extracranial venous anomalies are associated with changes in the intracranial physiology.

La formation des agrégats des peptides et des protéines par l'interaction de feuillets β a de plus en plus attiré l'attention car elle se produit dans de nombreuses maladies humaines généralisées, telles que la sclérose latérale amyotrophique (SLA), la maladie d'Alzheimer (AD), la maladie de Parkinson (PD), les maladies à prions et la maladie de Huntington (HD). La maladie d'Alzheimer est la forme la plus courante de démence qui provoque la perte de la mémoire chez les personnes âgées. En 2013, il y avait 35 millions de personnes souffrant de AD à travers le monde, un chiffre qui devrait doubler d'ici 2050. Etiologiquement ces maladies se manifestent par des dépôts anormaux de protéines, y compris les plaques neuritiques séniles (PNS) et les dégénérescences neurofibrillaires (DNF). L'accumulation extracellulaire d'agrégats insolubles de la protéine β-amyloide (A) conduit à la formation de plaques séniles, tandis que DNF se produisent à l’intérieur des neurones et sont composés par des filaments hélicoidaux appariés de la protéine tau hyperphosphorylée. Les peptides A sont produits en tant que monomères solubles et subissent l'oligomérisation et la formation de fibrilles amyloides par un processus qui n’a pas été complètement clarifié. Il est suggéré que les peptides Aß solubles jouent un rôle important dans la croissance neuronale, la survie et la modulation synaptique, tandis que les oligomères et fibrilles ont des propriétés toxiques. Une nouvelle stratégie thérapeutique vers la prévention ou le traitement de maladies associées à des structures -feuillet et, en particulier, AD, est représentée par la synthèse de mimes de -brins qui peuvent antagoniser la formation ou la reconnaissance de feuillet ß. En fait, dans la maladie d’Alzheimer, le processus d'agrégation des protéines implique une transition de la structure secondaire non ordonnée/α-hélice à une conformation riche en feuillet β, conduisant à la formation de feuillet croisés. Sur la base des quelques données publiées récemment sur des mimes d’épingles  et en particulier des structures macrocycliques de Nowick, comme inhibiteurs de l'agrégation des protéines, nous avons supposé qu’une pré-structuration des molécules peptidomimétiques pourrait augmenter leur affinité pour les peptides A et donc augmenter leur activité inhibitrice de l'agrégation. Notre conception vers un mime d’épingle stable, qui pourrait interagir et éventuellement agir en tant que ligand de feuillets β et inhibiteur de l'agrégation, implique l’assemblage d’une dicétopipérazine bifonctionnelle en tant que scaffold , d’un brin peptidomimétique pour stabiliser la formation de feuillets β et enfin d’une séquence peptidique convenable pour la liaison à la protéine. Ces molécules ont montré une interaction avec le peptide Aβ1-42 ainsi qu’une modulation de la cinétique d’agrégation. / The formation of peptide and protein aggregates through the interaction of β-sheets has increasingly drawn attention since it occurs in many widespread human diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson's disease (PD), prion diseases, and Huntington's disease (HD). Alzheimer’s disease is the most common form of dementia that causes memory loss in the elderly. In 2013, 35 million people were afflicted with AD worldwide, a number expected to double by 2050. Etiologically, the most common findings are abnormal protein deposits, including senile neuritic plaques (SNPs) and neurofibrillary tangles (NFTs). The extracellular accumulation of insoluble aggregates of β-amyloid protein (Aβ) leads to the formation of senile plaques, whereas NFTs occur intracellulary and are composed of paired helical filaments of hyperphosphorylated tau protein. Aβ peptides are produced as soluble monomers and undergo oligomerization and amyloid fibril formation via an unclear process. It is suggested that soluble A peptides play an important role in neuronal growth, survival, and synaptic modulation, while the oligomers and fibrils have toxic properties. Mimicking -strands to antagonize -sheet formation or recognition represent a new therapeutic strategy toward the prevention or treatment of diseases associated with -sheet structures such as AD. In this pathology, protein aggregation process involves a secondary structure transition from unordered/α-helix to a β-sheet rich conformation, leading to cross β-sheet structure formation. Based on the few recent published data on β-hairpin mimics, in particular on the macrocyclic structures of Nowick, as inhibitors of protein aggregation, we hypothesized that pre-structuring the peptidomimetic molecules might increase their affinity for Aβ peptides and thus increase their aggregation inhibitory activity. Our design towards a stable β-hairpin mimic (Figure 1), which could interact and eventually act as a β-sheet binder and aggregation inhibitor, involved assembling of a bifunctional diketopiperazine scaffold , a peptidomimetic strand to stabilize the formation of β-sheets and finally a suitable peptide sequence for binding to the aggregating protein. These molecules were shown to interact with the native Aβ1-42 peptide and modulate the kinetics of aggregation.

Les protéines amyloïdes sont impliquées dans de nombreux processus pathologiques de maladies qui restent souvent incurables. Ces protéines solubles dans leur forme native, s’auto- assemblent pour former des oligomères, des fibrilles, des fibres et enfin des agrégats riches en feuillets β. C’est ce processus délétère qui est le point commun entre ces maladies amyloïdes. La protéine amyloïde la plus décrite est le peptide Aβ suspecté de jouer un rôle primordial dans la maladie d’Alzheimer. Récemment, les petits oligomères du peptide Aβ1-42 formés lors des étapes précoces de ce processus ont été décrit comme étant les plus toxiques.Au cours de cette thèse, nous avons donc développé deux méthodes pour pouvoir évaluer l’activité des composés synthétisés sur les étapes précoces de l’oligomérisation et une pour étudier l’affinité du peptide Aβ1-42 pour son ligand. Nous avons également conçu et synthétisé des peptidomimétiques comme ligands du peptide Aβ1-42 capables ainsi de perturber les interactions protéine-protéine du processus d’agrégation du peptide Aβ1-42. L’évaluation de ces composés ainsi que de différents ligands synthétisés au laboratoire a permis une intéressante étude sur la relation entre la structure des composés évalués et leurs activités sur les étapes cruciales du processus d’oligomérisation du peptide Aβ1-42. Des études de viabilité cellulaire, de RMN et de Docking sont en cours pour améliorer notre compréhension du mode d’action de ces composés et du processus d’oligomérisation du peptide Aβ1-42. / Amyloid proteins are involved in many pathological processes of diseases that are often incurable. These soluble proteins in their native form self-assemble to form oligomers, fibrils, fibers and finally aggregates rich in β-sheets. It is this deleterious process which is the common point between these amyloid diseases. The most described amyloid protein is the Aß peptide suspected of playing a key role in Alzheimer's disease. Recently, small peptide Aβ1-42 oligomers formed during the early stages of this process have appeared to be the most toxic species.In this thesis, we have developed two methods to evaluate the activity of different synthesized compounds on the early steps of oligomerization and one method to study the affinity of Aβ1-42 peptide for its ligand. We have also designed and synthesized peptidomimetics as ligands of Aβ1-42 peptide which are able to disrupt protein-protein interactions involved in the aggregation process of Aβ1-42 peptide. Evaluation of these compounds as well as other ligands synthesized in the laboratory allowed an interesting study on the relationship between the structure of the tested compounds and their activities on the critical steps of the oligomerization process of Aβ1-42 peptide. Cell viability studies, NMR and docking are underway to improve our understanding of the mode of action of these compounds and of the oligomerization process of Aβ1-42 peptide.

Ce travail de thèse a permis la caractérisation de deux familles de modulateurs mitochondriaux: les analogues de l’alloprégnanolone et les nouveaux ligands synthétiques de la protéine de translocation mitochondriale ou translocator protein (TSPO) impliquée dans la neurostéroidogenèse. Nos résultats clés ont montré que: i) in vitro, BR297, un analogue de l'alloprégnanolone atténue les déficits bioénergétiques liés à la maladie d'Alzheimer et présente un effet protecteur contre le stress oxydatif, en réduisant les espèces réactives de l'oxygène et la mort dans un modèle cellulaire de la maladie d'Alzheimer, avec une plus grande efficacité comparé à l’allopregnanolone; ii) in vivo, premièrement l’effet protecteur de BR297 a été confirmé dans un modèle de souris transgénique de la maladie d’Alzheimer en atténuant les déficits mitochondriaux,puis deuxièmement, BR297 et BR351 ont démontré des effets neuroprotecteurs sur les dysfonctionnements mitochondriaux liés à l'âge par l'amélioration de bioénergétique cellulaire et des activités des complexes mitochondriaux; et iii) in vitro, les ligands TSPO représentent des molécules prometteuses qui sont capables d'augmenter bioénergétique cellulaire avec des effets comparable ou plus important que des molécules de référence dans un modèle cellulaire de la maladie d'Alzheimer. / This PhD work allowed the characterization of two families of mitochondrial modulators: novel analogues of allopregnanolone, and novel synthetic ligands of translocator protein (TSPO) implicated in the neurosteroidogenesis. Our key findings showed that: i) in vitro, BR297, an analog of allopregnanolone alleviated Alzheimer’s disease-related bioenergetics deficits and exhibited protective effects against oxidative stress by reducing reactive oxygen species and decreasing death in a cellular model of Alzheimer’s disease,with a higher effectiveness compared to allopregnanolone; ii) in vivo, firstly the protective effect of BR297 was confirmed in the transgenic Tg2576 mouse model by alleviating the mitochondrial deficits, secondly BR297and another analog BR351 demonstrated neuroprotective effects on age-related mitochondrial dysfunctions via enhancement of cellular bioenergetics and complex activities; and iii) in vitro, TSPO ligands represent promising molecules which are able to increase cellular bioenergetics with similar/ or higher effects compared to different reference molecules in a cellular model of Alzheimer’s disease.

La maladie d’Alzheimer (MA) est une maladie multifactorielle et à ce jour aucune cause des formes sporadiques de la maladie, qui représente plus de 99% des cas, n’a été mise en évidence. Des données émergentes de la littérature suggèrent l’existence d’un lien entre les dysfonctionnements thyroïdiens et la MA. Dans ce contexte, l’objectif de cette étude était de préciser l’implication de l’hypothyroïdie dans les processus neuropathologiques de la MA. En utilisant un modèle de rats rendus hypothyroïdiens par un traitement au propylthiouracile (PTU), nous avons montré que l’hypothyroïdie favorise la mise en place de lésions caractéristiques de la MA dans l’hippocampe, structure du cerveau précocement altérée dans la maladie et qui joue un rôle crucial dans les processus de mémoire. Une étude d’IRM in vivo a révélé une diminution progressive du volume cérébral des rats hypothyroïdiens. Dans l’hippocampe, l’hypothyroïdie s’accompagne d’une augmentation de la production de peptides amyloïdes, d’une hyperphosphorylation de la protéine Tau et d’une augmentation de la libération de plusieurs cytokines pro-Inflammatoires. Ces lésions, caractéristiques de la MA, sont associées à des troubles de la mémoire spatiale à court et long terme et à une altération de deux voies de signalisation connues pour jouer un rôle important dans les processus de plasticité synaptique et de mémoire : la voie calcique et la voie ERK-MAPK. Afin d’évaluer le potentiel de restauration de ces lésions, une partie des rats hypothyroïdiens a reçu des injections intra-Péritonéales de triiodothyronine (T3), forme active des hormones thyroïdiennes. Nos résultats montrent que l’administration de T3 permet de restaurer les déficits de mémoire spatiale à court terme, mais pas à long terme. En outre, ce même traitement permet de restaurer les niveaux de cytokines pro-Inflammatoires, de peptides amyloïdes ainsi que les voies « calcique » et « ERK-MAPK ». Ces données renforcent l’existence d’un lien entre l’hypothyroïdie et la MA : elles suggèrent que l’hypothyroïdie pourrait représenter un facteur important pouvant impacter le risque de développer des formes sporadiques de la MA. / Alzheimer’s disease (AD) is a multifactorial disease and to date no single cause for the sporadic forms, which accounts for over 99% of the cases, has been established. Converging evidence suggests a possible link between thyroid dysfunctions and AD. The aim of the present study was to explore the possibility that adult hypothyroidism represents an etiopathogenic mechanism of AD. In this context, using a hypothyroid rat model induced by propylthiouracil (PTU) treatment, we report that hypothyroidism is associated with several AD-Associated hallmarks in the hippocampus, a brain structure affected in early stages of AD and which plays a crucial role in memory processes. In vivo MRI revealed a progressive decrease in cerebral volume of hypothyroid-Rats. In the hippocampus, hypothyroidism resulted in Tau hyperphosphorylation, increased levels of amyloid peptide and of several pro-Inflammatory cytokines. These AD-Related pathological hallmarks were associated with impaired short- and long-Term spatial memory and alteration of hippocampal signalling pathways important for synaptic plasticity and memory, including calcium and ERK-MAPK pathways. To test the potential reversion of PTU-Induced lesions, we injected hypothyroid rats with triiodothyronine (T3), the active form of thyroid hormone. Our results show that intraperitoneal injections of T3 restored spatial short-Term, but not long-Term memory in hypothyroid-Treated rat. Furthermore, levels of pro-Inflammatory cytokines, amyloid peptide and of proteins involved in calcium and ERK-MAPK signalling were restored. These data strengthen the link between hypothyroidism and AD, supporting the idea that hypothyroidism may represent an important factor impacting the risk for developing sporadic forms of AD.

L’objectif principal de cette thèse est d’évaluer l’impact thérapeutique d’une intervention de stimulation cognitive associée à un programme d’activité physique au stade léger à modéré de la maladie d’Alzheimer. Précisément, il s’agit de détailler les effets respectifs et combinés de ces interventions selon les trois dimensions suivantes : 1) le fonctionnement cognitif général, 2) le fonctionnement exécutif à travers la mise à jour, l’alternance, l’inhibition et la planification, 3) le fonctionnement psychosocial, intégrant l’anxiété et la dépression. L’étude principale de cette thèse a comparé les performances pré- et post-intervention de 67 patients répartis en quatre groupes (i.e., groupe stimulation cognitive, groupe activité physique, groupe stimulation cognitive plus activité physique, groupe contrôle). Les résultats ont montré que, 1) la stimulation cognitive permet l’amélioration du fonctionnement cognitif général et le maintien des capacités d’alternance et de mise à jour, 2) l’activité physique favorise l’amélioration des capacités d’inhibition et le maintien des capacités d’alternance, et 3), l’association de la stimulation cognitive et de l’activité physique permet l’amélioration du fonctionnement cognitif général, l’amélioration des performances d’alternance et d’inhibition et le maintien des capacités de mise à jour. L’ensemble de ces résultats met en évidence le potentiel thérapeutique de la stimulation cognitive et de l’activité physique dans le traitement de la maladie d’Alzheimer. De plus, les données recueillies montrent que les bénéfices des interventions sont d’autant plus importants lorsque le programme intègre les deux formes de prises en charge. Les mécanismes par lesquels s’opèrent les changements dans la cognition des personnes souffrant d’Alzheimer sont discutés à travers le concept de réserve cognitive. L’enjeu des futures recherches réside dans le développement de thérapies visant le maintien du fonctionnement exécutif à travers la stimulation des capacités physiques et cognitives. / The principal objective of this thesis was to evaluate the therapeutic impact of an intervention which combines a cognitive stimulation program and a physical activity program in mild to moderate Alzheimer's disease. Specifically, the objective was to detail the respective and combined effects of these interventions in the three following dimensions, 1) general cognitive functioning, 2) executive functioning with updating, switching, inhibition and planning, 3) psychosocial functioning, including anxiety and depression. The main study of this thesis examines the pre-and post-intervention scores of 67 patients assigned into four groups (i.e., cognitive stimulation, physical activity, cognitive stimulation combined with physical activity, and control). The data showed that, 1) cognitive stimulation improved general cognitive functioning and maintained updating and switching abilities, 2) physical activity improved inhibition and switching abilities, and 3) associate cognitive stimulation and physical activity allowed the improvement of general cognitive functioning, inhibition and switching abilities, and allowed remaining updating abilities. Taken together, these results demonstrate the therapeutic effects of cognitive stimulation and physical activity in Alzheimer's disease treatment. Moreover, the data collected showed that the benefits of the interventions were particularly important when the program included both interventions. Mechanisms of changes in cognition of Alzheimer's patients are discussed through the concept of cognitive reserve. The aim for future researches is to develop programs of cognitive stimulation and physical activities to preserve executive functioning.

With 9.9 million new dementia cases each year, Alzheimer’s and Parkinson’s disease (AD and PD) are the most prevalent form of neurodegenerative disorder (NDG) affecting the aging population. Despite years of pharmaceutical research, no cure is yet available. Most neuropathological aspects of these diseases are extremely complex but the study of the rare genetic cases allowed to model these diseases in animals and uncover key pathophysiological processes. Transgenic Drosophila NDG models have been used for in vivo studies for many years with a range of relevant phenotypes. The cellular and molecular biology of the Central Nervous System, as well as the mechanisms underlying neurodegeneration, are well conserved between Drosophila and Humans (with a 75% of human disease-related genes having homologs in flies). Most NDG studies are performed in the aging flies. However, there are reports of measurable phenotypes for a variety of AD and PD models in juvenile Drosophila melanogaster (larval stage) with an unexploited considerable potential for drug discovery and screening for this outstanding model. Here I sought to develop a new assay for research into NDGs that focus on the earliest phenotypes. During this Ph.D. project a customized crawling assay apparatus was developed, for the assessment of locomotor ability in humanised larval Drosophila (overexpressing human proteins/peptides linked to AD and PD). A locomotor phenotype was identified in larvae overexpressing different variation of Amyloid-β42, tau and α-Synuclein pan neutrally: these animals crawl on agarose surface at a reduced mean speed when compared to controls. The defect was proven partially rescuable by administration of Tacrine and Methylene Blue, renewing the importance of such models for future applications in drug discovery and screening. The motor impairment supports the hypothesis of a neurotoxic effect of the protein/peptide. Thus, to test this further, the overexpression of the human transgenes was restricted to neurons involved in larval olfaction (olfactory impairment is often the earliest symptom in PD and AD) and odour associated learning tasks (both PD and AD are characterized by severe cognitive dysfunction). Interestingly, larvae overexpressing the Amyloid-β42 ARC peptide in the Olfactory Sensory Neurons showed a subtle navigation defect during chemotaxis (in 1-Hexanol odour gradient) that could possibly be addressed to premature neural habituation to the olfactory stimulus. Furthermore, the overexpression of the peptide in the larval Mushroom Bodies influenced the performances of the animals in associative learning tasks. Lastly, using immunohistochemistry and confocal imaging techniques I showed that the gross morphology of neurons is not altered by the targeted overexpression of the Amyloid-β42 ARC. Even though physiological studies are required to characterize the chemosensory/learning defect shown by the Amyloid-β42 ARC larvae, this Ph.D. work further confirms that the effects of the overexpression of the human transgenes are robust and measurable already at larval stage. These findings may also be relevant to the development of new, fast, and cost-effective compound screening procedures, for applications in early stages of the drug discovery process.

Alzheimer’s disease (AD) is the most common form of dementia and a growing disease burden that has seen pharmacological interventions primarily fail. Instead, it has been suggested that preventative measures such as a healthy diet may be the best way in preventing AD. Prebiotics are one such potential measure and are fermented into metabolites by the gut microbiota and acting as gut-brain axis components, beneficially impact the brain. However, the impact of prebiotics in AD prevention is unknown. Here we show that the prebiotic inulin increased multiple gut-brain axis components such as scyllo-inositol and short chain fatty acids in the gut, periphery, and in the case of scyllo-inositol, the brain. We found in E3FAD and E4FAD mice fed either a prebiotic or control diet for 4-months, that the consumption of the prebiotic inulin can beneficially alter the gut microbiota, modulate metabolic function, and dramatically increase scyllo-inositol in the brain. This suggests that the consumption of prebiotics can beneficially impact the brain by enhancing metabolism, helping to decrease AD risk factors.