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  Glial and vascular contributions to neurodegenerative diseases
  [1,2]. Here, we compared the coarse-grained plaque to other amyloid-β deposits by their regional distribution, association with APOE4, phosphorylated tau (pTau), and neuroinflammation.
The AD cohort (N=60; Braak tangle stage≥IV) was selected from the Mayo Clinic. Brain tissue from the middle frontal, superior temporal, and inferior parietal cortex was immunohistochemically stained for amyloid-β, pTau, CD68, and GFAP. Amyloid-β deposits including the coarse-grained plaque, the classic cored plaque, cerebral amyloid angiopathy (CAA-) Type-1 and Type-2 [3] were semi-quantitively scored. The cumulative deposit score, i.e., the sum of scores in all regions, was compared to the mean burden for each marker using Spearman’s ρ. The coarse-grained plaque was present in 75% of cases, of which 80% were APOE4. Coarse-grained plaque cases were younger at onset (p<0.05) and had a lower brain weight (p<0.05) than coarse-grained plaque negative cases. Coarse-grained plaques were correlated with amyloid-β (ρ=0.31*) and most interestingly with pTau (ρ=0.33**). Within APOE4, the coarse-grained plaque was additionally correlated with astrogliosis (ρ=0.31*). The classic cored plaque was present in all cases and equally in all regions. CAA-1 was present in 55% and CAA-2 in 87% of cases, both predominantly in the frontal and parietal cortex. Unlike the coarse-grained plaque, the classic cored plaque, CAA-1, and CAA-2 were not correlated with amyloid-β, pTau, GFAP, and CD68. More coarse-grained plaques are associated with fewer classic cored plaques (ρ=-0.42***) and more CAA-1 (ρ=0.33*).
The coarse-grained plaque, a distinct plaque type, is associated with increased pTau and within APOE4 with increased astrogliosis. Although overall amyloid-β is not well correlated with pTau tangles, distinct plaque-types are. To get to the root of AD etiology, research should investigate these finer differences in amyloid-β pathology.
Conclusion: Taken together, our findings suggest that loss of ABI3 function may increase the risk of developing AD by affecting amyloid-β accumulation and key microglia functions. These findings strengthen the disease-modifying role of microglia in AD.
Keywords: microglia, amyloid-β, migration, phagocytosis, single-cell RNA-seq
Cell metabolism orchestrates innate immune responses of microglial cells: Where do we stand and how we move forward? Novel insights on citrate cycle reprograming during microglial inflammatory activation
Canelif Yilmaz1, Eleftheria Karadima1, Georgia Fodelianaki1, Anupam Sinha1, Anke Witt2, Sofia Traikov3, Nicola Zamboni4, Alessandra Palladini5, Ünal Coskun5, Panayotis Verginis6, Mirko Peitzsch1, Triantafyllos Chavakis1, Vasileia-Ismini Alexaki1
1Institute of Clinical Chemistry and Laboratory Medicine, University Clinic, Medical Faculty, Technische Universität Dresden, Dresden, Germany, 2Department of Physiology, Medical Faculty, Technische Universität Dresden, Dresden, Germany, 3Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, 4Institute for Molecular Systems Biology, ETH Zurich, Zurich, Switzerland, 5Center for membrane biochemistry and lipid research, Technische Unversität Dresden, Dresden, Germany, 6Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
The role of ABI3 in microglia functions and the pathogenesis of Alzheimer’s disease
Hande Karahan1,2, Daniel C. Smith1, Byungwook Kim1,2, Luke C. Dabin1,2, Mamun Al-Amin1,2, Sagara Wijeratne1, Taylor Pennington1,2, Gonzalo Viana di Prisco1,2, Brianne McCord1,2, Peter Lin1, Adrian L. Oblak1,2, Shaoyou Chu1, Brady K. Atwood1,2, Jungsu Kim1,2
1Indiana University School of Medicine, Indianapolis, USA, 2Stark Neurosciences Research Institute, Indianapolis, USA
 Background: Recently, human genetics studies of Alzheimer’s disease (AD) have identified many risk variants in or near the genes that are highly or selectively expressed in microglia. However, how these AD risk genes regulate the function of microglia and contribute to the pathogenesis of AD remain unknown. One of these large-scale human genetics studies identified a rare coding variant in the Abelson interactor family member 3 (ABI3) gene locus and this variant was associated with increased risk of late-onset AD [1]. However, the role of ABI3 in the etiology of AD and its functions in the brain were unknown. Materials and Methods: To address these questions, we crossed Abi3 knock-out (Abi3-/-) mice with 5XFAD transgenic mouse model. We investigated the effect of loss of ABI3 function on pathological features of AD by using biochemical, histological, and functional approaches. Additionally, we performed transcriptomic analyses to identify the key pathways that are altered by Abi3 gene locus deletion. By using in vitro assays, we assessed how microglia functions are regulated by the Abi3 gene and how it may contribute to the disease pathogenesis.
Results: We demonstrated that amyloid-β levels were significantly increased whereas plaque-associated microglia were decreased in Abi3- /- mice. Additionally, we identified that the genes involved in microglial phagocytosis and immune response were dysregulated in Abi3-/- mice by using a gene expression panel. We also identified notable changes in the proportion of microglia subpopulations in Abi3-/- mice using a targeted single-cell RNA sequencing approach. Functional studies demonstrated that Abi3 knockdown impairs migration and phagocytosis of microglia in vitro.
In the recent years a great body of findings revealed that cell metabolism orchestrates immune responses from the cellular to the organismal level. Most of the studies concern monocytes/macrophages and T lymphocytes, which are immune cell populations easily isolated and cultured. In contrast, the study of cell metabolic adaptations in microglia has been so far hampered by several factors, such as the long process required for their isolation, the strong dependency of their phenotype and function on the central nervous system environment and the technical limitations of metabolomic analyses. Why is it important to better understand cell metabolism in microglia? How well can knowledge gained from the study of macrophages be transferred to microglia? And how can we improve the way to study microglial cell metabolism? These questions will be discussed on the basis of our own findings, which show that cell metabolism is rewired in microglia during inflammatory activation. Specifically, we describe a novel pathway connecting the citrate cycle and arginine metabolism, which tunes microglial inflammatory activation.
Brain extracellular vesicles reveal common molecular mechanisms of neuronal
insult between Alzheimer’s disease and Schizophrenia
Xavier Gallart-palau, Cristina Lorca1,2, Alina Onoiu1,
Aida Serra1,2
1Biomedical Research Institute of Lleida Dr. Pifarré Foundation (IRBLLEIDA) - +Pec Proteomics Research Group (+PPRG) - Neuroscience Area – University Hospital Arnau de Vilanova (HUAV), Xavier Gallart-Palau: [email protected], Lleida, 25198, Spain; , Lleida, Spain, 2IMDEA-Food Research Institute, Campus of International Excellence UAM+CSIC, Old Cantoblanco Hospital, 8 Crta. Canto Blanco, Madrid, Spain
 BACKGROUND: Extracellular vesicles have demonstrated implication in diverse molecular mechanisms of neuropathology in neurodegenerative brains [1]. However, it is unclear whether these implications are exclusive of dementia-related neurodegenerative events or may be shared with basic mechanisms of neuronal insult in other brain and mental illnesses such as Schizophrenia.

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