As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

Spinal Muscular Atrophy (SMA) is a neuronal degenerative disease caused by the mutation or loss of the Survival Motor Neuron (SMN) gene. The cause for the specific motor neuron susceptibility in SMA has not been identified. The high axonal transport/localization demand on motor neurons may be one potentially disrupted function, more specific to these cells. We therefore used a large-scale immunoprecipitation (IP) experiment, to identify potential interactors of SMN involved in neuronal transport and localization of mRNA targets. We identified KH-type splicing regulatory protein (KSRP), a multifunctional RNA-binding protein that has been implicated in transcriptional regulation, neuro-specific alternative splicing, and mRNA decay. KSRP is closely related to chick zipcode-binding protein 2 and rat MARTA1, proteins involved in neuronal transport/localization of beta-actin and microtubule-associated protein 2 mRNAs, respectively. We demonstrated that KSRP is arginine methylated, a novel SMN interactor (specifically with the SMN Tudor domain; and not with SMA causing mutants). We also found this protein to be misregulated in the absence of SMN, resulting in increased mRNA stability of KSRP mRNA target, p21cip/waf1. A role for SMN as an axonal chaperone of methylated RBPs could thus be key in SMA pathophysiology.

Os inibidores da enzima acetilcolinesterase constituem o principal tratamento da doença de Alzheimer e fontes de substâncias naturais com potencial anticolinesterásico vêm sendo amplamente estudadas. Dentre os frutos com benefícios para a saúde, a romã é evidenciada como excelente fonte de compostos antioxidantes, sendo que maior parte dos compostos se concentram em sua casca. Com base nisso, o objetivo desta pesquisa foi buscar novas substâncias naturais com potencial anticolinesterásico, através da avaliação de extratos de casca de romã. Quatro extratos com diferentes concentrações de etanol foram analisados quanto à atividade antioxidante, quantidade de compostos fenólicos, taninos e atividade anticolinesterásica. Do presente estudo foi constatado que a casca da romã apresentou elevada capacidade antioxidante, independente da concentração do solvente de extração empregado. O extrato formulado com 80% de etanol se destacou perante os demais pelo seu poder de inibição da acetilcolinesterase. Houve correlação negativa entre a atividade anticolinesterásica e a atividade antioxidante dos extratos. A atomização do extrato não acarretou mudanças em sua atividade anticolinesterásica e nem na sua capacidade antioxidante. Da mesma forma, a adição das micropartículas a um suco elaborado a partir de um preparado em pó não modificou suas características sensoriais. Diante do exposto, a elaboração de micropartículas de extrato de casca de romã constitui alternativa viável para a incorporação em diversos produtos, com a finalidade de prevenir ou reduzir risco da doença de Alzheimer. / The acetylcholinesterase inhibitors are the primary treatment of Alzheimer\'s disease and sources of natural substances with potential anticholinesterase have been widely studied. Among the fruits with health benefits, the pomegranate is evidenced as an excellent source of antioxidant compounds, and most compounds are concentrated in its peel. Based on this, the objective of this research was to find new substances with potential anticholinesterase, through the evaluation of pomegranate peel extracts. Four extracts with different concentrations of ethanol were analyzed for their antioxidant activity, amount of phenolic compounds, tannins and anticholinesterase activity. From this study it was found that pomegranate peel showed high antioxidant capacity, independent of the concentration of the solvent extraction employed. The extract formulated with 80% ethanol in relation to other stood out by his power of acetylcholinesterase inhibition. There was a negative correlation between acetylcholinesterase activity and antioxidant activity of the extracts. Microencapsulation of extract did not cause changes in their anticholinesterase activity and antioxidant capacity. The same way, the addition of microcapsules to a powder preparation for refreshment not changed their sensory characteristics. Given the above, the preparation of microcapsules of pomegranate peel extract is a viable alternative for incorporation into various products, in order to prevent or reduce risk of Alzheimer\'s disease.

Traumatic brain injury is a topic that in recent years has received increased scrutiny by the media and is viewed as a cause for public health concern in athletes that are participating in contact sports. There has been an apparent rise in the reported number of traumatic brain injuries over the last decade possibly due to a number of factors such as an increase in enrollment of sports and suspected better understanding of brain injury in the sports world. Direct or indirect impact forces applied involving acceleration/deceleration and linear/angular forces primarily cause trauma to the brain. This insult results in evident diffuse axonal and focal injuries to varying degrees in brain tissue. The spectrum of pathophysiology in traumatic brain injury involves structural, neurochemical, metabolic, vascular, inflammatory, immunologic, and ultimately cell death, which plays a hand directly in the nonspecific presentation of symptoms reported by athletes as well as the progression of recovery. Traumatic brain injury is typically associated with short- and long-term sequelae, however, inducing repetitive episodes of trauma over a career, as may happen in sports, may lead to a progressive neurodegenerative disease known as chronic traumatic encephalopathy. Chronic traumatic encephalopathy has been known to affect boxers previously, but in recent years the attention has shifted and found this disease in athletes from other sports. The spectrum of disease in chronic traumatic encephalopathy involves a progressive tauopathy that spreads across different regions of the brain in a classified four staged grading system. Several risk factors have been identified in placing athletes at risk for traumatic brain episodes, however no risk factors have been directly linked to chronic traumatic encephalopathy. Much information is lacking in a complete understanding of traumatic brain injury and chronic traumatic encephalopathy, therefore emphasizing the importance of further research and consistently improving modifications in the protocols for assessment, recognition, management, and return to play criteria for injured athletes. Furthermore, despite the gaps in knowledge, preventative measures should serve a particular role in reducing the incidence of detected traumatic brain injuries, which should include policy changes, sport rule changes, and especially changes to the accepted sports culture through mandatory education.

3. Summary Dissertation zur Erlangung des akademischen Grades Dr. rer. med. Cardiovascular risk factors in ageing brains: Functional and structural correlates of modifiable risk factors of brain ageing and Alzheimer’s disease among older individuals Eingereicht von: Shahrzad Kharabian Masouleh Angefertigt am: Max-Planck-Institut für Kognitions- und Neurowissenschaften, Abteilung für Neurologie, Leipzig Betreut von: Prof. Dr. med. Arno Villringer Dr. A. Veronica Witte March 2018 Due to a world-wide demographic change ageing-associated complications including cognitive impairments and neurodegenerative diseases such as dementia are becoming increasingly prevalent. In 2015, almost 47 million people worldwide were estimated to be affected by dementia, and the numbers are expected to reach 75 million by 2030, and 131 million by 2050, with the greatest increase expected in low-income and middle-income countries (Prince, M.; Wimo, A.; Guerchet, M.; Ali, G.; Wu, Y.; Prina, 2015). As no cure or substantial symptom-relieving treatment is yet available for these ever growing pathologic conditions, identifying modifiable factors that causally impact the risk of these diseases has become an important mission (Barnes and Yaffe, 2011). Although age is known to be the most important risk factor for these conditions, not all older individuals develop these pathologic states and pathologic neurodegenerative changes are not considered as part of a normal aging process. However, observations show that almost all aged brains show characteristic changes that are linked to neurodegeneration (Wyss-Coray, 2016). These observations raise the possibility that fundamental mechanisms of ageing may display early disease changes or contribute to the pathogenesis of neurodegenerative disorders (Bartzokis, 2011; Bishop et al., 2010; Raz, 2005). A better understanding of possible modulators of function and structure of brain in regions that are known to be vulnerable in aging would thus open a novel window towards targets for intervention of disease progression. Epidemiological studies have begun to identify many environmental and genetic risk factors that influence prevalence of neurodegenerative diseases in older ages. Importantly, with respect to Alzheimer’s disease (AD), conditions such as depression, obesity and hypertension, specifically in midlife and diabetes are shown to independently affect increased prevalence of AD worldwide. In 2010, fifteen thousand AD-cases world-wide were attributed to cigarette smoking and low physical or mental activity (Norton et al., 2014). Moreover, disadvantageous metabolic profiles such as higher blood glucose levels or lower high-density lipoprotein (HDL) levels have also been associated with worse cognition, brain alterations in AD-vulnerable regions and ultimately increased likelihood of developing AD in older ages (Crane et al., 2013; Villeneuve et al., 2014). In the first study of this thesis, we reviewed the epidemiological evidence regarding the impact of a “Mediterranean style diet” (MeDi) on brain health in aging (Huhn et al., 2015). MeDi, which is based on high consumption of fruits, vegetables, grains as well as sea-fish and low intake of sweets, convenient food, meat and dairy products, is shown to reduce cardio-vascular risk factors and benefit lipid and glucose metabolism while reducing risk of AD and cognitive dysfunction in aging. Despite extensive epidemiological evidence, little is known about neurobiological mechanisms, linking these life-style and health related factors to alterations in cognitive performance and incidence of AD. In the recent years whole brain magnetic resonance (MR) measurements have immensely increased our knowledge about the brain in health and disease. Novel MR protocols and analysis routines have been invented to assess different aspects of structure of the brain regions and their function within the living individuals. Studies in elderly AD patients have linked deposition of amyloid plaques, assessed using positron emission tomography (PET), in vulnerable structures such as frontal lobe, medial temporal structures and posterior cingulate area to atrophy and lower metabolic rate of glucose within these brain regions in association with accelerated cognitive decline (Buckner et al., 2005). Also, within healthy ageing population it has been shown that these AD-prone structures create a network, in which grey matter (GM) volume follow a different ageing trajectory compared to the rest of the brain, with a late development during adolescence and accelerated decline in older ages (Douaud et al., 2014; Fjell et al., 2014). Such coordinated change, specifically in older ages, might be a result of shared susceptibility of regions within this network to selective pathologies or a network-based spread of toxic agents (Zhou et al., 2012). Consequently, the above-mentioned AD-risk factors could through similar mechanisms impact brain structures within vulnerable regions, resulting in accelerated ageing, possibly reducing resilience of these regions towards AD-related pathology and thus increasing risk of developing AD in older ages. Based on this working hypothesis, in the rest of this doctoral research we investigate cerebral correlates of these risk factors and their impact on cognitive performance in healthy older adults. We initially focused on obesity as a major epidemic of the twentieth century, a major component of metabolic syndrome and an important AD-risk factor. Here we used conventional techniques to identify effects of Body-mass index (BMI) on regional GM volume (n = 617) as well as resting-state network connectivity (n = 712) and relations to cognitive performance in well-characterized samples of community-dwelled older adults (60-80 years) from Leipzig Research Centre for Civilization Diseases (LIFE) adult-study. The LIFE-Adult-Study is a population-based cohort study, which has already completed the baseline examination of 10,000 randomly selected participants from Leipzig, out of which ~2600 underwent a 3Tesla MRI brain scan, structured interviews, neuropsychological tests, and an extensive set of medical assessments (Loeffler et al., 2015). Our results showed that independent of age and a wide range of other confounding factors such as diabetes, hypertension, smoking status and APOE-genotype, there is a robust linear association between a higher BMI and lower GM volume in multiple brain regions, including (pre)frontal, temporal, insular and occipital cortex, thalamus, putamen, amygdala and cerebellum, which partially mediated negative effects of higher BMI on memory performance in our sample of older adults (Kharabian Masouleh et al., 2016). Furthermore, in the follow-up study, we found reproducible association between higher BMI and lower functional connectivity of the posterior cingulate cortex with other nodes of the default mode network (Beyer et al., 2017). This network that consists of AD-prone regions within frontal, temporal and parietal lobes, exhibits similar alterations in normal ageing and among patients with AD (Damoiseaux et al., 2012; Tomasi and Volkow, 2012). Inspired by our results on network-based functional connectivity alterations and in-line with the hypothesis of network-based spread of toxic agents in neurodegenerative diseases, in our third MRI-study, we extended the number of risk factors to cover major “modifiable” risk factors of AD and identified the potential impact of these factors on morphological properties of large-scale structural covariance networks (Kharabian Masouleh et al., 2017). We therefore systematically assessed independent effects of obesity, smoking, blood pressure, as well as markers of glucose and lipid metabolism and physical activity on major GM networks in the same cohort as our first MR study. Furthermore, we detailed our analysis by adding both BMI as well as waist-to-hip ratio as measures of obesity and identified the structural networks based on information on area, thickness and volume of cortical structures. The spatial extent and composition of the co-varying GM measures within the different networks indicated that smoking and, to a lesser degree, higher blood pressure affected GM throughout the brain, which might be attributed to direct and indirect damage of neuronal tissue. Higher glycosylated hemoglobin, as a long-term marker of glucose metabolism, was found to predominantly affect areas that are known to have high glucose metabolism and early A-beta deposition. In addition, we detected negative effects of visceral obesity on a structural network consisting of multimodal regions, covering areas rich in intracortical myelinated fibres. This network spatially recapitulated the pattern of brain atrophy observed in Alzheimer’s disease and has been previously shown to develop relatively slowly during adolescence but present “accelerated” age-related degeneration at an old age. Accordingly, our findings possibly point towards detrimental effects of visceral fat-induced low-grade inflammation on myelin. This is a hypothesis that we are going to test in our future studies in LIFE (by direct assessment of visceral fat (VAT) on abdominal MRI and inflammatory markers). Future longitudinal studies that incorporate more detailed microstructural assessments are now needed to prove our proposed neurobiological hypotheses on the underlying mechanisms of the observed effects and to test if improving cardiovascular risk, specifically visceral obesity, would help to maintain the integrity of GM networks throughout old age and reduce the risk of AD.:List of Abbreviations 3 List of Figures 4 List of Tables 5 1. Introduction: 6 1.1: “Normal” cognitive ageing: 9 1.1.1. Ageing-associated changes in brain structure and function: 9 1.2. Modifiers of brain ageing and AD: 11 1.3. Methods: 18 1.3.1. Imaging protocols: 18 1.3.2. Network Identification: 19 1.3.2.1. Resting-state fMRI network extraction 19 1.3.2.2. Grey matter structural network extraction 20 1.4. Rationale of the work: 23 2. Publications: 25 2.1. Publication1: Review: Huhn et al, 2015 25 2.2. Publication2: Original article: Kharabian et al, 2016 36 2.3. Publication3: Original article: Beyer et al, 2017 47 2.4. Publication4: Original article: Kharabian et al, 2017 62 3. Summary: 76 References: 83 A. Supplemental Materials 93 Publication2- Kharabian Masouleh et. al., 2016 93 Supplementary Tables for Publication2 97 Supplementary Figures for Publication 2 101 Supplementary Figures for Publication4 105 B. Declaration of Authenticity 106 C. Author contributions to the publications 107 D. Curriculum Vitae 114 E. List of Publications: 117 F. Acknowledgements 119

Les ataxies forment un groupe de maladies neurodégénératives qui sont caractérisées par un manque de coordination des mouvements volontaires. Mes travaux ont porté sur une forme d'ataxie à début tardif (LOCA), après l’âge de 50 ans. Les principales caractéristiques cliniques sont: atrophie cérébelleuse à l’IRM (88%), dysarthrie (81%), atrophie du lobe frontal (50%) et nystagmus (52%). La ségrégation dans les familles de cette ataxie est en faveur d’une transmission récessive. Afin d'identifier le gène responsable de LOCA, nous avons recruté 38 patients affectés d'une forme tardive d'ataxie, issus du SLSJ, des Cantons de l’Est ou d’autres régions du Québec. Un premier criblage du génome a été effectué avec des marqueurs microsatellites sur une famille clé. Une analyse de liaison paramétrique nous a suggéré une liaison au chromosome 13 (4.4Mb). Une recherche d’un haplotype partagé entre 17 familles LOCA a diminué la taille de l'intervalle candidat à 1.6Mb, mais l’haplotype s’est avéré fréquent dans la population canadienne-française. Un second criblage du génome avec des marqueurs SNP nous a permis d’évaluer par cartographie d’homozygotie la possibilité qu’une mutation fondatrice partagée dans des sous-groupes de malades. Plusieurs stratégies d'analyse ont été effectuées, entre autre par regroupement régional. Aucun loci candidats ne fut identifié avec confiance. Nous avons donc combiné les données de génotypage avec le séquençage exomique afin d'identifier le gène responsable. L'analyse de six individus atteints nous a permis d'obtenir une liste de variants rare contenant quatre gènes potentiels. Cette analyse doit se poursuivre pour identifier le gène responsable de LOCA. / Ataxias are a heterogeneous group of neurodegenerative diseases and are characterized by a lack of voluntary movements. My Master's project was on a late-onset ataxia (LOCA), after 50 years of age. The main clinical features are: cerebellar atrophy on MRI (88%), dysarthria (81%), frontal lobe atrophy (50%) and nystagmus (52%). Disease segregation in the family is suggestive of a recessive transmission. In order to identify the causal gene of LOCA, we have recruited 38 patients affected by a late-onset ataxia, originated from SLSJ, Eastern townships or other region in Quebec. A first genome scan was done with microsatellite markers on an informative family. Parametric linkage analysis suggested linkage on chromosome 13 (4.4Mb). Haplotype sharing analysis on 17 families reduced the candidate interval to 1.6Mb, but this haplotype was found to be frequent in the French-Canadian population. A second genome scan with SNPs markers allowed us to performed homozygozity mapping and look for founder mutations in subgroup of patients. Many strategies were performed, including regional clustering. No candidate loci were identified with confidence. We decided to combine the genotyping analysis results with exome sequencing to uncover the causative gene. The analysis on six affected individuals allowed us to obtain a rare variants list with four putative genes. More analysis is needed to identify the gene responsible for LOCA.

This review is a brief summary of the effects of nicotine on neural plasticity and behavior, with a focus on the preclinical literature and the effects of nicotine on neurotrophic factors. Focus areas include underlying mechanisms of nicotine addiction and the therapeutic potential for nicotine and nicotinic receptor agonists in Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, as well as cutting across these different areas of research with a brief review of the antiinflammatory effects of nicotine. It is clear that agonists at nicotinic receptors have therapeutic potential, but this should be weighed in the context of the effects of nicotine across the brain and its enhancement of neurotrophic factors. Although nicotine may have neuroprotective properties, it is important to keep in mind that these same effects underlie its addictive characteristics.

Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Using a forward genetic screen in Drosophila, we identified that loss of the Toll receptor adaptor dSarm (sterile a/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway. This death signaling pathway can be activated without injury by loss of the N-terminal self-inhibitory domain, resulting in spontaneous neurodegeneration. To investigate the role of axon self-destruction in disease, we assessed the effects of Sarm1 loss on neurodegeneration in the SOD1-G93A model of amyotrophic lateral sclerosis (ALS), a lethal condition resulting in progressive motor neuron death and paralysis. Loss of Sarm1 potently protects motor axons and synapses from degeneration, but only extends animal survival by 10%. Thus, there appears to be at least two driving forces in place during ALS disease progression: (1) Sarm1 mediated axon death, and (2) cell body destruction via some unknown mechanism.

Although the central nervous system was long perceived as the ivory tower without immune entities, there is growing evidence that the immune and nervous systems are intimated connected. These two systems have been shown to communicate both cellularly and molecularly under physiological and pathological conditions. Despite our increasing understanding of the interplay between these two systems, there are still numerous open questions. In this thesis, I address such unanswered questions related to: the role of microglia and their mechanism in contributing to pathologies in Rett syndrome; the beneficial effects of T-cell secreted cytokines in supporting social brain function; the evolutionary link of the interactions between the nervous and immune systems; the transcription regulation of a subset of microglia population in common neurodegenerative diseases. Collectively, the current thesis is focused on the joint frontier of bioinformatics and experimental work in neuroimmunology. A multifaceted approach, that includes transcriptomics, genomics and other biomolecular modules, was implemented to unearth signaling pathways and mechanisms underlying the presenting biological phenomena. The findings of this thesis can be summarized as follows: 1) MeCP2 acts as a master regulator in the transcriptional repression of inflammatory stimuli in macrophages; 2) T-cell secreted IFN-γ supports social brain function through an evolutionally conserved interaction between the immune and nervous systems; 3) The APOE-TREM2 pathway regulates the microglia phenotype switch in neurodegenerative diseases. Provided that recent technologies allow for readily manipulating the immune system, the findings presented herein may create new vistas for therapeutic interventions in various neurological disorders.

Les astrocytes sont des éléments clés de la physiologie cérébrale. Dans les maladies neurodégénératives comme la maladie d’Alzheimer (MA), les astrocytes deviennent réactifs. Cette réactivité astrocytaire (RA) est essentiellement caractérisée par des changements morphologiques. En revanche, les effets de la réactivité sur les fonctions de support des astrocytes sont mal connus. De plus, les cascades de signalisation qui conduisent à la RA restent à déterminer. Les objectifs de ce projet étaient de : 1/ démontrer que la voie JAK2-STAT3 (Janus Kinase 2 - Signal Transducer and Activator of Transcription 3) joue un rôle central dans le contrôle de la RA au cours des maladies neurodégénératives ; 2/ comprendre quelle est l’implication de la RA dans les altérations moléculaires, cellulaires et fonctionnelles observées dans la MA. Nous avons montré que la voie JAK2-STAT3 est une cascade de signalisation centrale dans la RA (Ben Haim et al., 2015). Dans ce projet, nous démontrons en utilisant de nouveaux outils moléculaires basés sur des vecteurs viraux, que cette voie est nécessaire et suffisante à la RA. Nos résultats montrent également que la modulation de la RA dans deux modèles murins de la MA (souris APP/PS1dE9 et 3xTg-AD) influence certains index pathologiques, mais de façon contexte-dépendante. L’ensemble de ce travail a permis de valider de nouveaux outils pour étudier les astrocytes réactifs in situ et souligne l’importance et la complexité de leur fonctions au cours des maladies neurodégénératives. / Astrocytes are emerging as key players in brain physiology. In Alzheimer’s disease (AD), astrocytes become reactive. Astrocyte reactivity (AR) is essentially characterized by morphological changes. But how the normal supportive functions of astrocytes are changed by their reactive state is unclear. Moreover, signaling cascades leading to AR are not yet determined. In this study, we aim to: 1/ demonstrate the JAK2-STAT3 pathway (Janus Kinase 2 - Signal Transducer and Activator of Transcription 3) is responsible for AR in neurodegenerative diseases ; 2/ understand the contribution of reactive astrocytes to molecular, cellular and functional alterations in AD. We already reported that the JAK2- STAT3 pathway is a central cascade for AR (Ben Haim et al., 2015). Here, we demonstrate, with new molecular tools based on viral vectors, that this pathway is necessary and sufficient to AR. Our results also show that the modulation of AR in two AD mouse models (APP/PS1dE9 and 3xTg-AD mice) influence several pathological hallmarks, but in a context-dependent manner. Overall, this work has generated new original tools to study reactive astrocytes in situ and it underlines the importance and complexity of their functions in neurodegenerative diseases.