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  Glial and vascular contributions to neurodegenerative diseases
Increased plasma and brain Immunoglobulin A in Alzheimer’s disease is lost in Apolipoprotein E4 carriers
Dovile Poceviciute1, Cristina Nuñez-Diaz1, Bodil Roth2, Shorena Janelidze1, The Netherlands Brain Bank3,
Andreas Giannisis4, Oskar Hansson5, Malin Wennström1
1Clinical Memory Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden, 2Department of Internal Medicine, Lund University, Skåne University Hospital, Malmö, Sweden, 3Netherlands Institute for Neuroscience, Amsterdam, The Netherlands, 4Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden, 5Memory Clinic, Skåne University Hospital, Malmö, Sweden
The role of alpha 2 adrenergic receptors in oxidative stress, beta amyloid/ tau pathology and neuroinflammation: an in vivo study in a triple transgenic model of Alzheimer’s disease Lusine Danielyan1,2,3, Daniela Lanvermann1, Margarita Mirumyan2, Magdalina M. Melkonyan4, Marine Buadze1, Libo Yu-Taeger5,6, Elisabeth Singer-Mikosch5,6, Lilit Hunanyan4, Gohar Karapetyan2, Ute Hofmann7, Matthias Schwab1,2,3,7, Konstantin Yenkoyan2, Huu Phuc Nguyen5
1University Hospital of Tuebingen, Department of Clinical Pharmacology, Tuebingen, Germany, 2Department of Biochemistry and Laboratory of Neuroscience, Cobrain Center, Yerevan State Medical University after Mkhitar Heratsi, Yerevan, Armenia, 3Department
of Clinical Pharmacology, Yerevan State Medical University after Mkhitar Heratsi, Yerevan, Armenia, 4Department of Medical Chemistry, Yerevan State Medical University after Mkhitar Heratsi, Yerevan, Armenia, 5Department of Human Genetics, University of Bochum, Bochum, Germany, 6Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany, 7Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart , Germany
 Background: Alzheimer’s disease (AD) is foremost characterized by β-amyloid (Aβ)-extracellular plaques, tau-intraneuronal fibrillary tangles (NFT), and neuroinflammation, but lately it has become evident that peripheral inflammation also contributes to the disease. AD patients often demonstrate increased levels of circulating proinflammatory mediators and altered antibody levels in the blood. In our study, we investigated plasma Immunoglobulin A (IgA) levels in association with apolipoprotein E (APOE) 4 status and Aβ pathology.
Methods: IgA levels in antemortem- (Cohort I) and postmortem- collected (Cohort II) plasma samples from AD patients (n=30 in Cohort I and n=16 in Cohort II) and non-demented controls (NC) (n=46 in Cohort I and n=7 in Cohort II) were measured using ELISA. Hippocampal sections from Cohort II were immunostained against IgA and the IgA area fraction as well as the number of IgA positive (IgA+) cells were analysed. The relationship between plasma IgA levels and cognition, inflammation, and cerebrospinal fluid (CSF) AD biomarkers in Cohort I as well as neuropathology, IgA+ cell number, and IgA area fraction in Cohort II was analysed before and after grouping the cohorts into APOE4-carriers and non-carriers.
Results: Plasma IgA levels were higher in AD patients compared to NC in both cohorts. Also, AD patients demonstrated higher IgA area fraction and IgA+ cell number compared to NC. When APOE4 status was considered, higher plasma IgA levels in AD patients were only seen in APOE4 non-carriers. Finally, plasma IgA levels, exclusively in APOE4 non-carriers, were associated with cognition, inflammation, and CSF Aβ levels in Cohort I as well as with IgA area fraction, IgA+ cell number, and Aβ, Lewy body, and NFT neuropathology in Cohort II.
Discussion: Our study suggests that AD pathology and cognitive decline are associated with increased plasma IgA levels in an APOE allele-dependent manner, where the associations are lost in APOE4- carriers.
Background: Noradrenergic deficit is considered to be a common hallmark of various neurodegenerative disorders including Alzheimer’s (AD) and Parkinson’s disease. One of the receptor systems capable of modulating noradrenaline (NA) content in the brain is alpha 2 adrenergic receptors (α2AR) which reduces NA level by inhibiting its release from presynaptic terminals. We sought to explore the impact of α2AR blockade by mesedin on the progression of the AD-like pathology in triple transgenic AD (3xTg-AD) mice.
Materials and Methods: Mesedin vs. vehicle treated aged (9-16 month old) 3xTg-AD mice were assessed for memory deficits (by T-maze), neuroinflammation and soluble beta amyloid (Aβ), oxidative stress markers, synaptic plasticity, Aβ generating and degrading enzymes by RNA sequencing, multiplex analysis, immunohistochemistry and Western Blots. Reactive oxygen species accumulation was evaluated by live cell imaging of astroglial primary culture (APC) from 3xTg-AD mice. Results: Mesedin-treated 3xTg-AD showed improved spatial working memory, increased expression of choline acetyltransferase and synaptophysin and reduced hippocampal Aβ plaque area, as well as reduced pro-inflammatory markers TNFα and IL-6. α2AR-blockade alleviated oxidative stress in vivo and in Aβ-exposed APC from 3xTg- AD mice. Total and phosphorylated tau and Aβ-generating enzymes remained unaffected while Aβ-degrading enzymes neprilysin and insulin degrading enzyme were increased.
Discussion: α2AR blockade leads to the slowed progression of AD hallmarks which is likely to be fulfilled by the complex interplay of blocked α2AR signaling and increased availability of NE to other α and β adrenergic receptor subtypes in the brain.
Conclusions: The complexity of α2AR involvement in AD-like pathology is reflected by its significant impact on oxidative stress, Aβ plaque pathology and neuroinflammation and can be therapeutically targeted by the α2AR-blocker mesedin.
Background: Human genetic data implicates microglia as critical players in neurodegenerative disease. In response, the field has focused on defining microglial transcriptional states across models
Interfering with Interferon-Responsive Microglia
Amanda McQuade1, Nina Drager1, Olivia Teter2, Kun Leng3, Martin Kampmann1,2,3
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Franscisco, USA, 2Department of Bioengineering, University of California, San Francisco, San Francisco, USA, 3Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, USA

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