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20Microglia are the tissue-resident macrophages of the central nervous system (CNS). Recent 21 studies based on bulk and single-cell RNA sequencing in mice indicate high relevance of 22 microglia with respect to risk genes and neuro-inflammation in Alzheimer's disease. Here, we 23 investigated microglia transcriptomes at bulk and single cell level in non-demented elderly and 24 AD donors using acute human post-mortem cortical brain samples. We identified 9 human 25 microglial subpopulations with heterogeneity in gene expression. Notably, gene expression 26 profiles and subcluster composition of microglia did not differ between AD donors and non-27 demented elderly in bulk RNA sequencing nor in single-cell sequencing. 28 human 30 31 Introduction 32Alzheimer's disease (AD), one of the most prevalent age-related neurodegenerative disorders, 33 is characterized by extracellular deposition of β-amyloid protein (Aβ) and intra-neuronal 34 neurofibrillary tangles in the neocortex [1]. 35Functional changes occurring in microglia cells have been proposed as an important factor in 36 AD pathology [2,3]. AD single nucleotide polymorphism (SNP) heritability was recently found 37 to be highly enriched in microglia enhancers [4]. Multiple genes associated with increased 38 susceptibility for sporadic AD are preferentially expressed in microglia, including APOE, CR1, 39 CD33, INPP5D, PLCG2, MS4A6A and TREM2 [5,6]. In AD mouse models, microglia have 40 been implicated in Aβ seeding, Aβ plaques are surrounded by activated microglia, microglia 41 protrusions physically interact with insoluble Aβ aggregates and microglia around plaques 42 undergo transcriptional changes [7-12]. Sustained depletion of microglia in 5xFAD mice 43 prevents Aβ plaque formation in parenchymal tissue, rather showing Aβ accumulation in the 44 brain vasculature [13]. The functional changes occurring in microglia during AD pathology 45seem to be diverse [14] and the exact role that microglia play in AD pathology is still unknown. 46 Many efforts have been made in AD mouse models to identify subpopulations of microglia that 47 are associated with AD pathology. A microglial neurodegenerative subpopulation was 48 discovered by Krasemann and colleagues that was associated with Aβ plaques and triggered by 49 phagocytosis of apoptotic neurons [9]. This transcriptional phenotype was characterized by 50 increased Spp1, Itgax, Axl, Lilrb4, Clec7a, Ccl2, Csf1, and Apoe and decreased P2ry12, 51 3 Tmem119, Olfml3, Csf1r, Rhob, Cx3cr1, Tgfb1, Mef2a, Mafb, and Sall1 expression levels [9]. 52 At the same time, a highly similar gene expression change, associated with microglia 53 surrounding Aβ plaques was reported by Keren-Shaul and colleagues [8], termed disease-54 associated microglia (DAMs). Using single-cell RNA-sequencing these DAMs were 55subdivided into two sequential stages, a Trem2-independent stage, marked by increased 56 expression of Tyrobp, Apoe, and B2m and decreased expression of homeostatic genes, followed 57 by a Trem2-dependent activation stage marked ...

The midbrain is an extensively studied brain region in schizophrenia, in view of its reported dopamine pathophysiology and neuroimmune changes associated with this disease. Besides the dopaminergic system, the midbrain contains other cell types that may be involved in schizophrenia pathophysiology. The neurovascular hypothesis of schizophrenia postulates that both the neurovasculature structure and the functioning of the blood-brain barrier (BBB) are compromised in schizophrenia. In the present study, potential alteration in the BBB of patients with schizophrenia was investigated by single-nucleus RNA sequencing of post-mortem midbrain tissue (15 schizophrenia cases and 14 matched controls). We did not identify changes in the relative abundance of the major BBB cell types, nor in the sub-populations, associated with schizophrenia. However, we identified 14 differentially expressed genes in the cells of the BBB in schizophrenia as compared to controls, including genes that have previously been related to schizophrenia, such as FOXP2 and PDE4D. These transcriptional changes were limited to the ependymal cells and pericytes, suggesting that the cells of the BBB are not broadly affected in schizophrenia.

The rodent olfactory bulb (OB) is continuously supplied with adult-born cells maturing into GABAergic neurons. Using in vivo ratiometric Ca 2+ imaging to readout ongoing and sensory-driven activity, we asked whether mature adult-born cells (mABCs) in the glomerular layer of the bulb become functionally identical to resident GABAergic (Res GABA) neurons. In awake head-restrained mice the two cell populations differed significantly in terms of ongoing spontaneous activity, with 24% of mABCs contributing to a strongly active cell cluster, absent among Res GABA cells. Odor-evoked responses of mABCs were sparse, less reliable, and had smaller amplitudes compared with Res GABA cells. The opposite was seen under anesthesia, with response reliability increasing and response size of mABCs becoming larger than that of Res GABA cells. Furthermore, ongoing activity of mABCs showed increased sensitivity to ketamine/xylazine and was selectively blocked by the antagonist of serotonin receptors methysergide. These functional features of mABCs clearly distinguish them from other OB interneurons.

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Multiple sclerosis (MS) is the most common inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. Chronicrelapsing experimental autoimmune encephalomyelitis (crEAE) in Biozzi ABH mice is an experimental model of MS. This crEAE model is characterized by an acute phase with severe neurological disability, followed by remission of disease, relapse of neurological disease and remission that eventually results in a chronic progressive phase that mimics the secondary progressive phase (SPEAE) of MS. In both MS and SPEAE, the role of microglia is poorly defined. We used a crEAE model to characterize microglia in the different phases of crEAE phases using morphometric and RNA sequencing analyses. At the initial, acute inflammation phase, microglia acquired a proinflammatory phenotype. At the remission phase, expression of standard immune activation genes was decreased while expression of genes associated with lipid metabolism and tissue remodeling were increased. Chronic phase microglia partially regain inflammatory gene sets and increase expression of genes associated with proliferation. Together, the data presented here indicate that microglia obtain different features at different stages of crEAE and a particularly mixed phenotype in the chronic stage. Understanding the properties of microglia that are present at the chronic phase of EAE will help to understand the role of microglia in secondary progressive MS, to better aid the development of therapies for this phase of the disease.

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