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      Alterations in dopamine system and in its connectivity with serotonin in a rat model of Alzheimer’s disease

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          Abstract

          Dopamine pathways alterations are reported in Alzheimer’s disease. However, it is difficult in humans to establish when these deficits appear and their impact in the course of Alzheimer’s disease. In the TgF344-Alzheimer’s disease rat model at the age of 6 months, we showed a reduction in in vivo release of striatal dopamine due to serotonin 5HT 2A-receptor blockade, in the absence of alterations in 5HT 2A-receptor binding, suggesting a reduction in 5HT 2A-receptor-dopamine system connectivity. In addition, a functional hypersensitivity of postsynaptic dopamine D 2-receptors and D 2-autoreceptors was also reported without any change in D 2-receptor density and in the absence of amyloid plaques or overexpression of the 18 kDa translocator protein (an inflammatory marker) in areas of the dopamine system. Citalopram, a selective serotonin reuptake inhibitor, induced functional 5HT 2A-receptor−D 2-receptor connectivity changes but had no effect on D 2-autoreceptor hypersensitivity. In older rats, dopamine cell bodies overexpressed translocator protein and dopamine projection sites accumulated amyloid. Interestingly, the 5HT 2A-receptor density is decreased in the accumbens subdivisions and the substantia nigra pars compacta. This reduction in the striatum is related to the astrocytic expression of 5HT 2A-receptor. Our results indicate that both serotonin/dopamine connectivity and dopamine signalling pathways are dysregulated and potentially represent novel early diagnostic and therapeutic avenues.

          Abstract

          Ceyzériat et al. demonstrate dysfunction in serotonin/dopamine connectivity and functional hypersensitivity of dopamine receptors in the TgF344-AD rat model of Alzheimer’s disease aged 6 months. Neurochemical alterations in serotonin receptor were also reported at an advanced age. Consequently, these results suggest dopamine and serotonin systems as new early-diagnostic and therapeutic avenues.

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          Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy

          Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the progressive loss of neurons, which typically leads to severe impairments in cognitive functions including memory and learning. Key pathological features of this disease include the deposition of highly insoluble amyloid β peptides and the formation of neurofibrillary tangles (NFTs) in the brain. Mounting evidence also implicates sustained glial-mediated inflammation as a major contributor of the neurodegenerative processes and cognitive deficits observed in AD. Methods This paper provides an overview of findings from both human and animal studies investigating the role of microglia and astrocytes in AD, and discusses potential avenues for therapeutic intervention. Results Glial-mediated inflammation is a ‘double-edged sword’, performing both detrimental and beneficial functions in AD. Despite tremendous effort in elucidating the molecular and cellular mechanisms underlying AD pathology, to date, there is no treatment that could prevent or cure this disease. Current treatments are only useful in slowing down the progression of AD and helping patients manage some of their behavioral and cognitive symptoms. Conclusion A better understanding of the role of microglia and astrocytes in the regulation of AD pathology is needed as this could pave the way for new therapeutic strategies.
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            Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease

            Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.
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              A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss.

              Alzheimer's disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The "amyloid cascade hypothesis" posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.
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                Author and article information

                Journal
                Brain Commun
                Brain Commun
                braincomms
                Brain Communications
                Oxford University Press
                2632-1297
                2021
                10 March 2021
                10 March 2021
                : 3
                : 2
                : fcab029
                Affiliations
                [1 ] Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva , 1206 Geneva, Switzerland
                [2 ] Division of Nuclear medicine, Diagnostic Department, University Hospitals and Geneva University of Geneva , 1206 Geneva, Switzerland
                [3 ] Division of Radiation Oncology, Department of Oncology, University Hospitals of Geneva , 1206 Geneva, Switzerland
                [4 ] Normandie University, UNICAEN, Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN) , 14000 Caen, France
                [5 ] Department of Nuclear Medicine, CHU Cote de Nacre , 14000 Caen, France
                [6 ] Normandie University, UNICAEN, IMOGERE , 14000 Caen, France
                [7 ] Department of Psychiatry, University of Geneva , Geneva, Switzerland
                Author notes
                Correspondence to: Benjamin B. Tournier, PhD Division of Adult Psychiatry, University Hospitals of Geneva Avenue de la Roseraie, 64, 1206 Geneva, Switzerland E-mail: benjamin.tournier@ 123456hcuge.ch
                Author information
                https://orcid.org/0000-0002-6565-6313
                https://orcid.org/0000-0001-7583-1894
                https://orcid.org/0000-0002-5262-4494
                https://orcid.org/0000-0002-5803-0478
                https://orcid.org/0000-0002-8027-7530
                Article
                fcab029
                10.1093/braincomms/fcab029
                8287930
                34286270
                4dbe9c96-8b79-4a54-b6a2-5ebf307de372
                © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 December 2020
                : 20 January 2021
                : 22 January 2021
                Page count
                Pages: 16
                Funding
                Funded by: “Maria Zaousi” Memorial Foundation through the Greek State Scholarship Foundation and the Jean and Madeleine Vachoux Foundation;
                Funded by: Velux Foundation, DOI 10.13039/100007214;
                Award ID: 1123
                Funded by: Rat Resource and Research Center (RRRC, Columbia);
                Funded by: “Swiss Association for Alzheimer's Research”;
                Funded by: Swiss fundamental and clinical research programs on Alzheimer's disease;
                Categories
                Original Article

                alzheimer’s disease,d2 receptor,5ht2a receptor,amyloid,tspo

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