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      The Major Risk Factors for Alzheimer's Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques.

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          Abstract

          Gene expression profiles of more than 10,000 individual microglial cells isolated from cortex and hippocampus of male and female AppNL-G-F mice over time demonstrate that progressive amyloid-β accumulation accelerates two main activated microglia states that are also present during normal aging. Activated response microglia (ARMs) are composed of specialized subgroups overexpressing MHC type II and putative tissue repair genes (Dkk2, Gpnmb, and Spp1) and are strongly enriched with Alzheimer's disease (AD) risk genes. Microglia from female mice progress faster in this activation trajectory. Similar activated states are also found in a second AD model and in human brain. Apoe, the major genetic risk factor for AD, regulates the ARMs but not the interferon response microglia (IRMs). Thus, the ARMs response is the converging point for aging, sex, and genetic AD risk factors.

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          Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

          E H Corder, A M Saunders, W J Strittmatter … (1993)
          The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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            TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.

            Irene Tom, Yuanyuan Wang, Lino C Gonzalez … (2016)
            Genetic variants of TREM2, a protein expressed selectively by microglia in the brain, are associated with Alzheimer's disease (AD). Starting from an unbiased protein microarray screen, we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2. Binding of these ligands by TREM2 was abolished or reduced by disease-associated mutations. Overexpression of wild-type TREM2 was sufficient to enhance uptake of LDL, CLU, and APOE in heterologous cells, whereas TREM2 disease variants were impaired in this activity. Trem2 knockout microglia showed reduced internalization of LDL and CLU. β-amyloid (Aβ) binds to lipoproteins and this complex is efficiently taken up by microglia in a TREM2-dependent fashion. Uptake of Aβ-lipoprotein complexes was reduced in macrophages from human subjects carrying a TREM2 AD variant. These data link three genetic risk factors for AD and reveal a possible mechanism by which mutant TREM2 increases risk of AD. VIDEO ABSTRACT.
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              Microglial signatures and their role in health and disease

              Oleg Butovsky, Howard Weiner (2018)
              Microglia are the primary innate immune cells in the CNS. In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages. In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment.
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Cell Rep
                Title: Cell reports
                Publisher: Elsevier BV
                ISSN (Electronic): 2211-1247
                Publication date (Electronic): April 23 2019
                Volume: 27
                Issue: 4
                Affiliations
                [1 ] VIB Centre for Brain Disease Research, Leuven, Belgium; University of Leuven, Department of Neurosciences and Leuven Brain Institute, Leuven, Belgium; UK Dementia Research Institute, University College London, London, UK. Electronic address: carlo.salafrigerio@kuleuven.vib.be.
                [2 ] VIB Centre for Brain Disease Research, Leuven, Belgium; University of Leuven, Department of Neurosciences and Leuven Brain Institute, Leuven, Belgium.
                [3 ] Foundational Neuroscience Center, AbbVie, Inc., Cambridge, MA, USA.
                [4 ] Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
                [5 ] Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
                [6 ] UK Dementia Research Institute, University College London, London, UK; Centre for Biological Sciences, University of Southampton, Southampton, UK.
                [7 ] VIB Centre for Brain Disease Research, Leuven, Belgium; University of Leuven, Department of Neurosciences and Leuven Brain Institute, Leuven, Belgium; UK Dementia Research Institute, University College London, London, UK. Electronic address: bart.destrooper@kuleuven.vib.be.
                Article
                Publisher Item ID: S2211-1247(19)30438-3
                DOI: 10.1016/j.celrep.2019.03.099
                PubMed ID: 31018141
                SO-VID: 956ffb9b-5483-463c-8b28-804a3801c33c
                History

                Keywords: single cell sequencing,IRM,single cell RNA-seq,app knock in,Alzheimer,apoe,in situ RNA hybridization,microglia,ARM
                Data availability:
                Keywords: single cell sequencing, IRM, single cell RNA-seq, app knock in, Alzheimer, apoe, in situ RNA hybridization, microglia, ARM

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